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Goggin KE, Seo SJ, Wu BG, Ivelja S, Kugler MC, Chang M, Darawshy F, Li Y, Chung CJ, Kyeremateng Y, Tsay JCJ, Singh S, Sterman DH, Segal LN, Egilmez NK, Li Q. Differential Effects of High-Fiber and Low-Fiber Diets on Antitumor Immunity and Colon Tumor Progression in a Murine Model. Cancer Prev Res (Phila) 2025; 18:223-234. [PMID: 39911064 PMCID: PMC12053542 DOI: 10.1158/1940-6207.capr-24-0159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/12/2024] [Accepted: 02/04/2025] [Indexed: 02/07/2025]
Abstract
The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on antitumor immunity and the gut microbiota in APCmin/+ mice infected with enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and the tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared with chow diet. However, the low-fiber diet significantly reduced the tumor burden and improved survival. Mechanistically, high fiber increased proinflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, whereas low fiber enhanced anti-inflammatory cytokines and cytotoxic T cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ regulatory T cells and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management. Prevention Relevance: Dietary fiber's impact on colon cancer progression highlights the need for personalized dietary approaches, considering microbial infection and immune status.
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Affiliation(s)
- Kevin E Goggin
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202
| | - SeonYeong Jamie Seo
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202
| | - Benjamin G. Wu
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
- Division of Pulmonary and Critical Care Medicine, Veterans Affairs (VA) New York Harbor Healthcare System, New York, NY 10006
| | - Sinisa Ivelja
- Department of Pathology, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Matthias C Kugler
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Miao Chang
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Fares Darawshy
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Yonghua Li
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Cecilia J. Chung
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Yaa Kyeremateng
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Jun-Chieh J. Tsay
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
- Division of Pulmonary and Critical Care Medicine, Veterans Affairs (VA) New York Harbor Healthcare System, New York, NY 10006
| | - Shivani Singh
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Daniel H Sterman
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
| | - Leopoldo N Segal
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 10006
| | - Nejat K Egilmez
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202
| | - Qingsheng Li
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York University (NYU) Langone Health, New York, NY 10006
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202
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Tripathi S, Sharma Y, Kumar D. Unveiling the link between chronic inflammation and cancer. Metabol Open 2025; 25:100347. [PMID: 39876904 PMCID: PMC11772974 DOI: 10.1016/j.metop.2025.100347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025] Open
Abstract
The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.
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Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
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Kim SY, Koh JY, Lee DH, Kim HD, Choi SJ, Ko YY, Lee HS, Lee JS, Choi IA, Lee EY, Jeong HW, Jung MK, Park SH, Park JY, Kim W, Shin EC. Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals. J Hepatol 2024; 81:806-818. [PMID: 38879170 DOI: 10.1016/j.jhep.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND & AIMS Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment. METHODS Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis. RESULTS The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance. CONCLUSIONS Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection. IMPACT AND IMPLICATIONS During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.
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Affiliation(s)
- So-Young Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - June-Young Koh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34051, Republic of Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Republic of Korea
| | - Hyung-Don Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Seong Jin Choi
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Yun Yeong Ko
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
| | - Ha Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jeong Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34051, Republic of Korea
| | - In Ah Choi
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hye Won Jeong
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea
| | - Min Kyung Jung
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Republic of Korea.
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea.
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Anvar MT, Rashidan K, Arsam N, Rasouli-Saravani A, Yadegari H, Ahmadi A, Asgari Z, Vanan AG, Ghorbaninezhad F, Tahmasebi S. Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies? Cancer Cell Int 2024; 24:355. [PMID: 39465401 PMCID: PMC11514949 DOI: 10.1186/s12935-024-03525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.
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Affiliation(s)
- Milad Taghizadeh Anvar
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimiya Rashidan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Arsam
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ashkan Rasouli-Saravani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Yadegari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Ahmadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeynab Asgari
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Ghorbani Vanan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farid Ghorbaninezhad
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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5
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Ak Ç, Sayar Z, Thibault G, Burlingame EA, Kuykendall MJ, Eng J, Chitsazan A, Chin K, Adey AC, Boniface C, Spellman PT, Thomas GV, Kopp RP, Demir E, Chang YH, Stavrinides V, Eksi SE. Multiplex imaging of localized prostate tumors reveals altered spatial organization of AR-positive cells in the microenvironment. iScience 2024; 27:110668. [PMID: 39246442 PMCID: PMC11379676 DOI: 10.1016/j.isci.2024.110668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/19/2024] [Accepted: 08/01/2024] [Indexed: 09/10/2024] Open
Abstract
Mapping the spatial interactions of cancer, immune, and stromal cell states presents novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate cancer cells, the impact of spatial stromal cell heterogeneity remains poorly understood. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of single cells and recurrent cellular neighborhoods in the prostate tumor microenvironment of treatment-naive patients. We report unique populations of mast cells that show distinct spatial associations with M2 macrophages and regulatory T cells. Our results show disease-specific neighborhoods that are primarily driven by androgen receptor-positive (AR+) stromal cells and identify inflammatory gene networks active in AR+ prostate stroma.
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Affiliation(s)
- Çiğdem Ak
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | - Zeynep Sayar
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | - Guillaume Thibault
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | - Erik A Burlingame
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | - M J Kuykendall
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Jennifer Eng
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | - Alex Chitsazan
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Koei Chin
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Andrew C Adey
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Christopher Boniface
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Paul T Spellman
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - George V Thomas
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Pathology & Laboratory Medicine, School of Medicine, OHSU, Portland, OR 97239, USA
| | - Ryan P Kopp
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Urology, School of Medicine, Knight Cancer Institute, Portland, OR 97239, USA
| | - Emek Demir
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Division of Oncological Sciences, School of Medicine, OHSU, Portland, OR 97239, USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
| | | | - Sebnem Ece Eksi
- Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, OHSU, Portland, OR 97209, USA
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Wei Q, Chen R, He X, Qu Y, Yan C, Liu X, Liu J, Luo J, Yu Z, Hu W, Wang L, Lin X, Wu C, Xiao J, Zhou H, Wang J, Zhu M, Yang P, Chen Y, Tan Q, Yuan X, Jing H, Zhang W. Multi-omics and single cell characterization of cancer immunosenescence landscape. Sci Data 2024; 11:739. [PMID: 38972884 PMCID: PMC11228048 DOI: 10.1038/s41597-024-03562-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 06/21/2024] [Indexed: 07/09/2024] Open
Abstract
Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ ).
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Affiliation(s)
- Qiuxia Wei
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Ruizhi Chen
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
- Gannan Medical University, Ganzhou, 341000, China
- Suichang County People's Hospital, Lishui, 323000, China
| | - Xue He
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Yanan Qu
- Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China
| | - Changjian Yan
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Xiaoni Liu
- Department of Respiratory Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Jing Liu
- Gannan Medical University, Ganzhou, 341000, China
| | - Jiahao Luo
- Gannan Medical University, Ganzhou, 341000, China
| | - Zining Yu
- Department of Clinical Laboratory, Shangrao Municipal Hospital, Jiangxi, 334000, China
| | - Wenping Hu
- Gannan Medical University, Ganzhou, 341000, China
| | - Liqun Wang
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Xiaoya Lin
- Gannan Medical University, Ganzhou, 341000, China
| | - Chaoling Wu
- Department of Respiratory medicine, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China
| | - Jinyuan Xiao
- Gannan Medical University, Ganzhou, 341000, China
| | - Haibo Zhou
- Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Jing Wang
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Mingxia Zhu
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Ping Yang
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Yingtong Chen
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China
| | - Qilong Tan
- School of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Xiaoliang Yuan
- Department of Respiratory Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
| | - Hongmei Jing
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China.
| | - Weilong Zhang
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, China.
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7
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Honing DY, Luiten RM, Matos TR. Regulatory T Cell Dysfunction in Autoimmune Diseases. Int J Mol Sci 2024; 25:7171. [PMID: 39000278 PMCID: PMC11241405 DOI: 10.3390/ijms25137171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Regulatory T cells (Tregs), a suppressive subpopulation of T cells, are potent mediators of peripheral tolerance, responsible for immune homeostasis. Many autoimmune diseases exhibit disruptions in Treg function or quantity, resulting in an imbalance between protective and pathogenic immune cells. Selective expansion or manipulation of Tregs is a promising therapeutic approach for autoimmune diseases. However, the extensive diversity of Treg subpopulations and the multiple approaches used for Treg identification leads to high complexity, making it difficult to develop a successful treatment capable of modulating Tregs. In this review, we describe the suppressive mechanisms, subpopulations, classification, and identification methodology for Tregs, and their role in the pathogenesis of autoimmune diseases.
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Affiliation(s)
- Dionne Y Honing
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Rosalie M Luiten
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Tiago R Matos
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Sanofi, 1105 BP Amsterdam, The Netherlands
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Wang Z, Chang Y, Sun H, Li Y, Tang T. Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review). Oncol Lett 2024; 27:257. [PMID: 38646499 PMCID: PMC11027113 DOI: 10.3892/ol.2024.14390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 03/15/2024] [Indexed: 04/23/2024] Open
Abstract
The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.
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Affiliation(s)
- Zhi Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yu Chang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haibo Sun
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yuqin Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Tongyu Tang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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Cheng C, Liang S, Yue K, Wu N, Li Z, Dong T, Dong X, Ling M, Jiang Q, Liu J, Huang XJ. STAT5 is essential for inducing the suppressive subset and attenuate cytotoxicity of Vδ2 + T cells in acute myeloid leukemia. Cancer Lett 2024; 587:216730. [PMID: 38360140 DOI: 10.1016/j.canlet.2024.216730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/04/2024] [Accepted: 02/10/2024] [Indexed: 02/17/2024]
Abstract
Under the sustained exposure to tumor microenvironment, effector lymphocytes may transform into the suppressive populations. γδ T cells are recognized as a crucial mediator and effector of immune surveillance and thereby a promising candidate for anti-tumor immunotherapy. Emerging clinical studies implicate that some γδ T subsets play an important role in promoting tumor progression. Our previous study identified an abnormal Vδ2+ T cells subset with regulatory features (Reg-Vδ2) in the patients with newly diagnosed acute myeloid leukemia (AML), and demonstrated that Reg-Vδ2 cells significantly suppressed the anti-AML effects of effector Vδ2 cells (Eff-Vδ2). The molecular mechanism underlying the subset transformation of Vδ2 cells remains unclear. Here, we found that the expression and activity of STAT5 were significantly induced in Reg-Vδ2 cells compared with Eff-Vδ2 cells, which was consistent with the differences found in primary Vδ2 cells between AML patients and healthy donors. In-vitro experiments further indicated that STAT5 was required for the induction of Reg-Vδ2 cells. The combined immunophenotypical and functional assays showed that blockage of STAT5 alleviated the immunosuppressive effect of Reg-Vδ2 cells on Eff-Vδ2 cells and enhanced the anti-AML capacity of Vδ2 cells from health donors and AML patients. Collectively, these results suggest that STAT5 acts as a critical regulator in the transformation of effector Vδ2 cells into a subset with immunosuppressive characteristics, providing a potential target for the improvement the efficacy of γδ T cells-based immunotherapy to treat AML and other hematologic malignancies.
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Affiliation(s)
- Cong Cheng
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (2019RU029), Beijing, China
| | - Shuang Liang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Keli Yue
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Ning Wu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Zongru Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Tianhui Dong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xinyu Dong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Min Ling
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Qian Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Jiangying Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (2019RU029), Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
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10
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Langyue H, Ying Z, Jianfeng J, Yue Z, Huici Y, Hongyan L. IRF4-mediated Treg phenotype switching can aggravate hyperoxia-induced alveolar epithelial cell injury. BMC Pulm Med 2024; 24:130. [PMID: 38491484 PMCID: PMC10941512 DOI: 10.1186/s12890-024-02940-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 03/01/2024] [Indexed: 03/18/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is characterized by alveolar dysplasia, and evidence indicates that interferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various inflammatory lung diseases. Nonetheless, the significance and mechanism of IRF4 in BPD remain unelucidated. Consequently, we established a mouse model of BPD through hyperoxia exposure, and ELISA was employed to measure interleukin-17 A (IL-17 A) and interleukin-6 (IL-6) expression levels in lung tissues. Western blotting was adopted to determine the expression of IRF4, surfactant protein C (SP-C), and podoplanin (T1α) in lung tissues. Flow cytometry was utilized for analyzing the percentages of FOXP3+ regulatory T cells (Tregs) and FOXP3+RORγt+ Tregs in CD4+ T cells in lung tissues to clarify the underlying mechanism. Our findings revealed that BPD mice exhibited disordered lung tissue structure, elevated IRF4 expression, decreased SP-C and T1α expression, increased IL-17 A and IL-6 levels, reduced proportion of FOXP3+ Tregs, and increased proportion of FOXP3+RORγt+ Tregs. For the purpose of further elucidating the effect of IRF4 on Treg phenotype switching induced by hyperoxia in lung tissues, we exposed neonatal mice with IRF4 knockout to hyperoxia. These mice exhibited regular lung tissue structure, increased proportion of FOXP3+ Tregs, reduced proportion of FOXP3+RORγt+ Tregs, elevated SP-C and T1α expression, and decreased IL-17 A and IL-6 levels. In conclusion, our findings demonstrate that IRF4-mediated Treg phenotype switching in lung tissues exacerbates alveolar epithelial cell injury under hyperoxia exposure.
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Affiliation(s)
- He Langyue
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Zhu Ying
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Jiang Jianfeng
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Zhu Yue
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Yao Huici
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Lu Hongyan
- Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China.
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11
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Cui H, Wang N, Li H, Bian Y, Wen W, Kong X, Wang F. The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology. Cell Commun Signal 2024; 22:99. [PMID: 38317142 PMCID: PMC10845554 DOI: 10.1186/s12964-024-01505-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/28/2024] [Indexed: 02/07/2024] Open
Abstract
The changes in T regulatory cell (Treg) and T helper cell (Th) 17 ratios holds paramount importance in ensuring internal homeostasis and disease progression. Recently, novel subsets of Treg and Th17, namely IL-17-producing Treg and IL-10-producing Th17 have been identified. IL-17-producing Treg and IL-10-producing Th17 are widely considered as the intermediates during Treg/Th17 transformation. These "bi-functional" cells exhibit plasticity and have been demonstrated with important roles in multiple physiological functions and disease processes. Yin and Yang represent opposing aspects of phenomena according to the ancient Chinese philosophy "Yin-Yang" theory. Furthermore, Yin can transform into Yang, and vice versa, under specific conditions. This theory has been widely used to describe the contrasting functions of immune cells and molecules. Therefore, immune-activating populations (Th17, M1 macrophage, etc.) and immune overreaction (inflammation, autoimmunity) can be considered Yang, while immunosuppressive populations (Treg, M2 macrophage, etc.) and immunosuppression (tumor, immunodeficiency) can be considered Yin. However, another important connotation of "Yin-Yang" theory, the conversion between Yin and Yang, has been rarely documented in immune studies. The discovery of IL-17-producing Treg and IL-10-producing Th17 enriches the meaning of "Yin-Yang" theory and further promotes the relationship between ancient "Yin-Yang" theory and modern immunology. Besides, illustrating the functions of IL-17-producing Treg and IL-10-producing Th17 and mechanisms governing their differentiation provides valuable insights into the mechanisms underlying the dynamically changing statement of immune statement in health and diseases.
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Affiliation(s)
- Huantian Cui
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Ning Wang
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Hanzhou Li
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yuhong Bian
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Weibo Wen
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Xiangying Kong
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Fudi Wang
- The First Affiliated Hospital, Institute of Translational Medicine, The Second Affiliated Hospital, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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12
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Ge L, Xu M, Huang M, Liu S, Zhou Z, Xia Z, Zhao Q, Zhou F. Sirtuin2 suppresses the polarization of regulatory T cells toward T helper 17 cells through repressing the expression of signal transducer and activator of transcription 3 in a mouse colitis model. Immun Inflamm Dis 2024; 12:e1160. [PMID: 38415949 PMCID: PMC10836035 DOI: 10.1002/iid3.1160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 02/29/2024] Open
Abstract
INTRODUCTION Regulatory T cells (Tregs) play an important role in inflammatory bowel diseases (IBDs) through modulating intestinal inflammation. However, the factors affecting Treg function and plasticity during IBD progression are not thoroughly disclosed. The current study aims to reveal new molecular mechanisms affecting Treg plasticity. METHODS A mouse strain, in which tdTomato and enhanced green fluorescent protein were under the control of the Foxp3 promoter and Il17a promoter, was established and subjected to colitis induction with dextran sulfate sodium. The existence of Tregs and IL-17-expressing Tregs (i.e., Treg/T helper 17 [Th17] cells) were observed and sorted from the spleen, mesenteric lymph nodes, and lamina propria by flow cytometry, followed by measuring Sirtuin2 (Sirt2) expression using quantitative reverse transcription polymerase chain reaction and Immunoblotting. Lentivirus-induced Sirt2 silencing was applied to determine the impact of Sirt2 on Treg polarization to Treg/Th17 cells and even Th17 cells. The effect of Sirt2 on Stat3 was analyzed by flow cytometry and immunoblotting. RESULTS Sirt2 was highly expressed in lamina propria Tregs and it moderately suppressed Foxp3 expression as well as the immunosuppressive function of Tregs. Surprisingly, lentivirus-mediated Sirt2 silencing promoted the generation of Treg/Th17 cells out of Tregs. Sirt2 silencing also enhanced the generation of Th17 cells out of Tregs under the Th17 induction condition. Furthermore, Sirt2 inhibited Th17 induction by suppressing the protein level of the signal transducer and activator of transcription 3. CONCLUSION Sirt2 suppresses Treg function but also inhibits Treg polarization toward Treg/Th17 cells and Th17 cells. The ultimate effect of Sirt2 on colitis might depend on the balance among Tregs, Treg/Th17 cells, and Th17 cells.
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Affiliation(s)
- Liuqing Ge
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Min Xu
- Department of Hematology and Oncology, Wuhan Children's Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Meifang Huang
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Shaoping Liu
- Medical Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zhidai Zhou
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Ziqin Xia
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Qiu Zhao
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Feng Zhou
- Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal DiseasesZhongnan Hospital of Wuhan UniversityWuhanChina
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13
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Paz Del Socorro T, Oka K, Boulard O, Takahashi M, Poulin LF, Hayashi A, Chamaillard M. The biotherapeutic Clostridium butyricum MIYAIRI 588 strain potentiates enterotropism of Rorγt +Treg and PD-1 blockade efficacy. Gut Microbes 2024; 16:2315631. [PMID: 38385162 PMCID: PMC10885180 DOI: 10.1080/19490976.2024.2315631] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 02/02/2024] [Indexed: 02/23/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) have been positioned as a standard of care for patients with advanced non-small-cell lung carcinomas (NSCLC). A pilot clinical trial has reflected optimistic association between supplementation with Clostridium butyricum MIYAIRI 588 (CBM588) and ICI efficacy in NSCLC. However, it remains to be established whether this biotherapeutic strain may be sufficient to heighten the immunogenicity of the tumor draining lymph nodes to overcome resistance to ICI. Herein, we report that supplementation with CBM588 led to an improved responsiveness to antibody targeting programmed cell death protein 1 (aPD-1). This was statistically associated with a significant decrease in α-diversity of gut microbiota from CBM588-treated mice upon PD-1 blockade. At the level of the tumor-draining lymph node, such combination of treatment significantly lowered the frequency of microbiota-modulated subset of regulatory T cells that express Retinoic Orphan Receptor gamma t (Rorγ t+ Treg). Specifically, this strongly immunosuppressive was negatively correlated with the abundance of bacteria that belong to the family of Ruminococcaceae. Accordingly, the colonic expression of both indoleamine 2,3-Dioxygenase 1 (IDO-1) and interleukin-10 (IL-10) were heightened in mice with greater PD-1 blockade efficacy. The CBM588-induced ability to secrete Interleukin-10 of lamina propria mononuclear cells was heightened in tumor bearers when compared with cancer-free mice. Conversely, blockade of interleukin-10 signaling preferentially enhanced the capacity of CD8+ T cells to secrete Interferon gamma when being cocultured with CBM588-primed lamina propria mononuclear cells of tumor-bearing mice. Our results demonstrate that CBM588-centered intervention can adequately improve intestinal homeostasis and efficiently overcome resistance to PD-1 blockade in mice.
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Affiliation(s)
| | - Kentaro Oka
- R&D Division, Miyarisan Pharmaceutical Co., Ltd, Saitama, Japan
| | | | | | | | - Atsushi Hayashi
- R&D Division, Miyarisan Pharmaceutical Co., Ltd, Saitama, Japan
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14
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Ramanan D, Chowdhary K, Candéias SM, Sassone-Corsi M, Gelineau A, Mathis D, Benoist C. Homeostatic, repertoire and transcriptional relationships between colon T regulatory cell subsets. Proc Natl Acad Sci U S A 2023; 120:e2311566120. [PMID: 38064511 PMCID: PMC10723124 DOI: 10.1073/pnas.2311566120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/26/2023] [Indexed: 12/17/2023] Open
Abstract
Foxp3+ regulatory T cells (Tregs) in the colon are key to promoting peaceful coexistence with symbiotic microbes. Differentiated in either thymic or peripheral locations, and modulated by microbes and other cellular influencers, colonic Treg subsets have been identified through key transcription factors (TFs; Helios, Rorγ, Gata3, and cMaf), but their interrelationships are unclear. Applying a multimodal array of immunologic, genomic, and microbiological assays, we find more overlap than expected between populations. The key TFs (Rorγ, Helios, Gata3, and cMaf) play different roles, some essential for subset identity, others driving functional gene signatures. Functional divergence was clearest under challenge. Single-cell genomics revealed a spectrum of phenotypes between the Helios+ and Rorγ+ poles, different Treg-inducing bacteria inducing the same Treg phenotypes to varying degrees, not distinct populations. TCR repertoires in monocolonized mice revealed that Helios+ and Rorγ+ Tregs are related and cannot be uniquely equated to tTreg and pTreg. Comparison of spleen and colon repertoires revealed that 2 to 5% of clonotypes are shared between the locations. We propose that rather than the origin of their differentiation, tissue-specific cues dictate the spectrum of colonic Treg phenotypes.
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Affiliation(s)
| | | | - Serge M. Candéias
- Université Grenoble Alpes, Commissariat à l’Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, Interdisciplinary Research Institute of Grenoble, Laboratory of Chemistry and Biology of Metals, Grenoble38054, France
| | | | | | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA02115
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15
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Ramanan D, Pratama A, Zhu Y, Venezia O, Sassone-Corsi M, Chowdhary K, Galván-Peña S, Sefik E, Brown C, Gélineau A, Mathis D, Benoist C. Regulatory T cells in the face of the intestinal microbiota. Nat Rev Immunol 2023; 23:749-762. [PMID: 37316560 DOI: 10.1038/s41577-023-00890-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2023] [Indexed: 06/16/2023]
Abstract
Regulatory T cells (Treg cells) are key players in ensuring a peaceful coexistence with microorganisms and food antigens at intestinal borders. Startling new information has appeared in recent years on their diversity, the importance of the transcription factor FOXP3, how T cell receptors influence their fate and the unexpected and varied cellular partners that influence Treg cell homeostatic setpoints. We also revisit some tenets, maintained by the echo chambers of Reviews, that rest on uncertain foundations or are a subject of debate.
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Affiliation(s)
| | - Alvin Pratama
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Yangyang Zhu
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Olivia Venezia
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Esen Sefik
- Department of Immunology, Yale University, New Haven, CT, USA
| | - Chrysothemis Brown
- Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Paediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA
| | | | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA, USA
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16
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Huangfu L, Li R, Huang Y, Wang S. The IL-17 family in diseases: from bench to bedside. Signal Transduct Target Ther 2023; 8:402. [PMID: 37816755 PMCID: PMC10564932 DOI: 10.1038/s41392-023-01620-3] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/16/2023] [Accepted: 08/22/2023] [Indexed: 10/12/2023] Open
Abstract
The interleukin-17 (IL-17) family comprises six members (IL-17A-17F), and recently, all of its related receptors have been discovered. IL-17 was first discovered approximately 30 years ago. Members of this family have various biological functions, including driving an inflammatory cascade during infections and autoimmune diseases, as well as boosting protective immunity against various pathogens. IL-17 is a highly versatile proinflammatory cytokine necessary for vital processes including host immune defenses, tissue repair, inflammatory disease pathogenesis, and cancer progression. However, how IL-17 performs these functions remains controversial. The multifunctional properties of IL-17 have attracted research interest, and emerging data have gradually improved our understanding of the IL-17 signaling pathway. However, a comprehensive review is required to understand its role in both host defense functions and pathogenesis in the body. This review can aid researchers in better understanding the mechanisms underlying IL-17's roles in vivo and provide a theoretical basis for future studies aiming to regulate IL-17 expression and function. This review discusses recent progress in understanding the IL-17 signaling pathway and its physiological roles. In addition, we present the mechanism underlying IL-17's role in various pathologies, particularly, in IL-17-induced systemic lupus erythematosus and IL-17-related tumor cell transformation and metastasis. In addition, we have briefly discussed promising developments in the diagnosis and treatment of autoimmune diseases and tumors.
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Affiliation(s)
- Longjie Huangfu
- School of Stomatology, Harbin Medical University, Harbin, 150001, P. R. China
| | - Ruiying Li
- Department of Oral Pathology, School of Stomatology, Hainan Medical University, Haikou, 571199, P. R. China
| | - Yamei Huang
- Department of Oral Pathology, School of Stomatology, Hainan Medical University, Haikou, 571199, P. R. China
| | - Shan Wang
- Department of Oral Pathology, School of Stomatology, Hainan Medical University, Haikou, 571199, P. R. China.
- Department of Stomatology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570216, P. R. China.
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17
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Herrnstadt GR, Niehus CB, Ramcke T, Hagenstein J, Ehnold LI, Nosko A, Warkotsch MT, Feindt FC, Melderis S, Paust HJ, Sivayoganathan V, Jauch-Speer SL, Wong MN, Indenbirken D, Krebs CF, Huber TB, Panzer U, Puelles VG, Kluger MA, Steinmetz OM. The CCR6/CCL20 axis expands RORγt + Tregs to protect from glomerulonephritis. Kidney Int 2023; 104:74-89. [PMID: 36924892 DOI: 10.1016/j.kint.2023.02.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 03/17/2023]
Abstract
Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.
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Affiliation(s)
- Georg R Herrnstadt
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph B Niehus
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Torben Ramcke
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Hagenstein
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura-Isabell Ehnold
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Nosko
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias T Warkotsch
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frederic C Feindt
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Melderis
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Joachim Paust
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Varshi Sivayoganathan
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Milagros N Wong
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf Panzer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Victor G Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malte A Kluger
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver M Steinmetz
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Fidelle M, Rauber C, Alves Costa Silva C, Tian AL, Lahmar I, de La Varende ALM, Zhao L, Thelemaque C, Lebhar I, Messaoudene M, Pizzato E, Birebent R, Mbogning Fonkou MD, Zoppi S, Reni A, Dalban C, Leduc M, Ferrere G, Durand S, Ly P, Silvin A, Mulder K, Dutertre CA, Ginhoux F, Yonekura S, Roberti MP, Tidjani-Alou M, Terrisse S, Chen J, Kepp O, Schippers A, Wagner N, Suárez-Gosálvez J, Kobold S, Fahrner JE, Richard C, Bosq J, Lordello L, Vitali G, Galleron N, Quinquis B, Le Chatelier E, Blanchard L, Girard JP, Jarry A, Gervois N, Godefroy E, Labarrière N, Koschny R, Daillère R, Besse B, Truntzer C, Ghiringhelli F, Coatnoan N, Mhanna V, Klatzmann D, Drubay D, Albiges L, Thomas AM, Segata N, Danlos FX, Marabelle A, Routy B, Derosa L, Kroemer G, Zitvogel L. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science 2023; 380:eabo2296. [PMID: 37289890 DOI: 10.1126/science.abo2296] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/14/2023] [Indexed: 06/10/2023]
Abstract
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.
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Affiliation(s)
- Marine Fidelle
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Conrad Rauber
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Department of Gastroenterology and Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Carolina Alves Costa Silva
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Ai-Ling Tian
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Imran Lahmar
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Anne-Laure Mallard de La Varende
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Liwei Zhao
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Cassandra Thelemaque
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Isabelle Lebhar
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Meriem Messaoudene
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada
| | - Eugenie Pizzato
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Roxanne Birebent
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Maxime Descartes Mbogning Fonkou
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Silvia Zoppi
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Anna Reni
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Cécile Dalban
- Clinical Research Department, Centre Léon Bérard, Lyon, France
| | - Marion Leduc
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Gladys Ferrere
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- EverImmune, Gustave Roussy Cancer Campus, Villejuif Cedex, France
| | - Sylvère Durand
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Pierre Ly
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France
| | - Aymeric Silvin
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Kevin Mulder
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Charles-Antoine Dutertre
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Florent Ginhoux
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Satoru Yonekura
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Maria Paula Roberti
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD), Heidelberg, Germany
| | - Maryam Tidjani-Alou
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Safae Terrisse
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Jianzhou Chen
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Oliver Kepp
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Angela Schippers
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | - Norbert Wagner
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | - Javier Suárez-Gosálvez
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Jean-Eudes Fahrner
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Corentin Richard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada
| | | | - Leonardo Lordello
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
| | - Giacomo Vitali
- MetaGenoPolis, INRAe, Université Paris-Saclay, Jouy en Josas, France
| | - Nathalie Galleron
- MetaGenoPolis, INRAe, Université Paris-Saclay, Jouy en Josas, France
| | - Benoît Quinquis
- MetaGenoPolis, INRAe, Université Paris-Saclay, Jouy en Josas, France
| | | | - Lucas Blanchard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Anne Jarry
- Nantes Université, Université d'Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France
| | - Nadine Gervois
- Nantes Université, Université d'Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France
| | - Emmanuelle Godefroy
- Nantes Université, Université d'Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France
| | - Nathalie Labarrière
- Nantes Université, Université d'Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France
- LabEx IGO, Université de Nantes, Nantes, France
| | - Ronald Koschny
- Department of Gastroenterology and Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Romain Daillère
- EverImmune, Gustave Roussy Cancer Campus, Villejuif Cedex, France
| | - Benjamin Besse
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
| | - Caroline Truntzer
- Université de Bourgogne Franche-Comté, Plateforme de Transfert de Biologie du Cancer, Centre Georges-François Leclerc, Equipe Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, Institut Médical de Génétique et d'Immunologie, Dijon, France
| | - François Ghiringhelli
- Université de Bourgogne Franche-Comté, Plateforme de Transfert de Biologie du Cancer, Centre Georges-François Leclerc, Equipe Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, Institut Médical de Génétique et d'Immunologie, Dijon, France
| | - Nicolas Coatnoan
- AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France
- Sorbonne Université, INSERM, UMRS959 Immunology-Immunopathology-Immunotherapy Laboratory, Paris, France
| | - Vanessa Mhanna
- AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France
- Sorbonne Université, INSERM, UMRS959 Immunology-Immunopathology-Immunotherapy Laboratory, Paris, France
| | - David Klatzmann
- AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France
- Sorbonne Université, INSERM, UMRS959 Immunology-Immunopathology-Immunotherapy Laboratory, Paris, France
| | - Damien Drubay
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Office of Biostatistics and Epidemiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
- Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif, France
| | - Laurence Albiges
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
| | - Andrew Maltez Thomas
- Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy
| | - Nicola Segata
- Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy
- Istituto Europeo di Oncologia (IEO), National Cancer Institute (IRCCS), Milan, Italy
| | - François-Xavier Danlos
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France
- Drug Development Department, Gustave Roussy Cancer Campus, Villejuif Cedex, France
| | - Aurélien Marabelle
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France
- Drug Development Department, Gustave Roussy Cancer Campus, Villejuif Cedex, France
| | - Bertrand Routy
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada
- Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Quebec, Canada
| | - Lisa Derosa
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif Cedex, France
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France
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Agalioti T, Cortesi F, Gagliani N. T H17 cell immune adaptation. Curr Opin Immunol 2023; 83:102333. [PMID: 37172412 DOI: 10.1016/j.coi.2023.102333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/25/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023]
Abstract
At mucosal barriers, the T helper 17 (TH17) cell population plays a fundamental role in controlling tissue homeostasis. The adaptability of this population to a more pro-inflammatory or anti-inflammatory function - that is, their functional plasticity and consequently heterogeneity - primarily depends on the environment. We would like to term this process environmental immune adaptation. Interfering with TH17 cell adaptation leads to pathological consequences, including development of immune-mediated inflammatory diseases or even cancer. Several molecular mechanisms have been shown to participate in this process and recently, a better understanding of the transcriptional and metabolic profiling of TH17 cells has shed light on a new level of complexity. Here, we offer a summary on the role of TH17 cell plasticity in inflammatory diseases and cancer as well as the latest discoveries and controversies regarding the mechanisms that control the adaptability of the TH17 cell population.
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Affiliation(s)
- Theodora Agalioti
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Filippo Cortesi
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Nicola Gagliani
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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Yan Y, Li K, Jiang J, Jiang L, Ma X, Ai F, Qiu S, Si W. Perinatal tissue-derived exosomes ameliorate colitis in mice by regulating the Foxp3 + Treg cells and gut microbiota. Stem Cell Res Ther 2023; 14:43. [PMID: 36941715 PMCID: PMC10029206 DOI: 10.1186/s13287-023-03263-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/06/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND The capacity of self-renewal and multipotent differentiation makes mesenchymal stem cells (MSC) one of the most widely investigated cell lines in preclinical studies as cell-based therapies. However, the low survival rate and poor homing efficiency of MSCs after transplantation hinder the therapeutic application. Exosomes derived from MSCs have shown promising therapeutic potential in many diseases. However, the heterogeneity of MSCs may lead to differences in the function of secreting exosomes. In this study, the therapeutic effects of hUC-Exos and hFP-Exos on the DSS-induced colitis mouse model were investigated. METHODS The colitis mouse models were randomly divided into four groups: (1) DSS administered for 7 days and euthanasia (DSS7D), (2) DSS administered for 7 days and kept for another 7 days without any treatment (DSS14D), (3) DSS administered for 7 days and followed with hUC-EVs infusion for 7 days (hUC-EVs) and (4) DSS administered for 7 days and followed with hFP-EVs infusion for 7 days (hFP-EVs). We analyzed colon length, histopathology, Treg cells, cytokines and gut microbiota composition in each group. RESULTS A large amount of IL-6, IL-17 and IFN-γ were produced along with the decrease in the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells in DSS7D group, which indicated that Th17 cells were activated and Treg cells were suppressed. We found that the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells increased in order to suppress inflammation, but the length of colon did not recover and the symotoms were worsened of the colonic tissue in DSS14D group. The subsequent infusion of either hUC-Exos or hFP-Exos mediated the transformation of Treg and Th17 cells in colitis mice to maintain immune balance. The infusion of hUC-Exos and hFP-Exos also both reduced the abundance of pro-inflammatory intestinal bacterial such as Verrucomicrobia and Akkermansia muciniphila to improve colitis. CONCLUSIONS We found that Foxp3 + Treg cells can inhibit the inflammatory response, and the over-activated Treg cells can still further damage the intestinal mucosa. hUC-Exos and hFP-Exos can control inflammation by regulating the balance between Th17 cells and Treg cells. Decreased inflammatory response improved the structure of colon wall in mice and reduced the abundance of pro-inflammatory bacteria in the intestine. The improvement of intestinal wall structure provides conditions for the reproduction of beneficial bacteria, which further contributes to the reduction of colitis.
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Affiliation(s)
- Yaping Yan
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Kaixiu Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Jiang Jiang
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Lihong Jiang
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Key Laboratory of Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
| | - Xiang Ma
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Fang Ai
- Department of Obstetrics, The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Shuai Qiu
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Wei Si
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
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Zhang C, Zeng C, Xiong S, Zhao Z, Wu G. A mitophagy-related gene signature associated with prognosis and immune microenvironment in colorectal cancer. Sci Rep 2022; 12:18688. [PMID: 36333388 PMCID: PMC9636133 DOI: 10.1038/s41598-022-23463-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and one of the most prevalent malignancies worldwide. Previous research has demonstrated that mitophagy is crucial to developing colorectal cancer. This study aims to examine the association between mitophagy-related genes and the prognosis of CRC patients. Gene expression profiles and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) regression analysis were applied to establish a prognostic signature using mitophagy related genes. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to analyze patient survival and predictive accuracy. Meanwhile, we also used the Genomics of Drug Sensitivity in Cancer (GDSC) database and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to estimate the sensitivity of chemotherapy, targeted therapy and immunotherapy. ATG14 overexpression plasmid was used to regulate the ATG14 expression level in HCT116 and SW480 cell lines, and cell counting kit-8, colony formation and transwell migration assay were performed to validate the function of ATG14 in CRC cells. A total of 22 mitophagy-driven genes connected with CRC survival were identified, and then a novel prognostic signature was established based on 10 of them (AMBRA1, ATG14, MAP1LC3A, MAP1LC3B, OPTN, VDAC1, ATG5, CSNK2A2, MFN1, TOMM22). Patients were divided into high-risk and low-risk groups based on the median risk score, and the survival of patients in the high-risk group was significantly shorter in both the training cohort and two independent cohorts. ROC curve showed that the area under the curves (AUC) of 1-, 3- and 5-year survival were 0.66, 0.66 and 0.64, respectively. Multivariate Cox regression analysis confirmed the independent prognostic value of the signature. Then we constructed a Nomogram combining the risk score, age and M stage, which had a concordance index of survival prediction of 0.77 (95% CI 0.71-0.83) and more robust predictive accuracy. Results showed that CD8+ T cells, regulatory T cells and activated NK cells were significantly more enriched in the high-risk group. Furthermore, patients in the high-risk group are more sensitive to targeted therapy or chemotherapy, including bosutinib, elesclomol, lenalidomide, midostaurin, pazopanib and sunitinib, while the low-risk group is more likely to benefit from immunotherapy. Finally, in vitro study confirmed the oncogenic significance of ATG14 in both HCT116 and SW480 cells, whose overexpression increased CRC cell proliferation, colony formation, and migration. In conclusion, we developed a novel mitophagy-related gene signature that can be utilized not only as an independent predictive biomarker but also as a tool for tailoring personalizing treatment for CRC patients, and we confirmed ATG14 as a novel oncogene in CRC.
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Affiliation(s)
- Cong Zhang
- grid.415440.0Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Cailing Zeng
- grid.415440.0Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Shaoquan Xiong
- grid.415440.0Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Zewei Zhao
- grid.411304.30000 0001 0376 205XChengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Guoyu Wu
- grid.415440.0Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
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22
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Saberzadeh-Ardestani B, Foster NR, Lee HE, Shi Q, Alberts SR, Smyrk TC, Sinicrope FA. Association of tumor-infiltrating lymphocytes with survival depends on primary tumor sidedness in stage III colon cancers (NCCTG N0147) [Alliance]. Ann Oncol 2022; 33:1159-1167. [PMID: 35963480 PMCID: PMC9882989 DOI: 10.1016/j.annonc.2022.07.1942] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are a robust and independent prognostic variable in localized colon cancer. Given reported differences in molecular features and prognosis of right- versus left-sided tumors, we examined the association of TIL densities with patient survival by primary tumor sidedness in stage III cancers, including clinical low- (T1-3, N1) and high-risk (T4 and/or N2) groups. PATIENTS AND METHODS In a phase III trial of FOLFOX-based adjuvant chemotherapy, TIL densities were analyzed and dichotomized in colon carcinomas (N = 1532) based on a previously determined cut point optimized for disease-free survival (DFS). Right-sided tumors were defined as proximal to the splenic flexure. Associations of TILs and sidedness with 5-year DFS were examined using Kaplan-Meier methodology along with multivariable modeling and relative contribution analysis by Cox regression. RESULTS Lower TIL densities were found in left- versus right-sided tumors (P < 0.0001). The association of TIL densities with DFS differed significantly by tumor sidedness (Pinteraction = 0.045). Overall, patient tumors with low (versus high) TILs had significantly poorer DFS in right-sided (hazard ratio 2.02, 95% confidence interval 1.45-2.82; Padj < 0.0001), but not left-sided tumors (Padj = 0.1731). Among clinical low-risk patients, low (versus high) TILs were adversely prognostic only in right-sided tumors (Padj = 0.0058). Among high-risk patients, low TILs were prognostic independent of sidedness (Padj < 0.025). The relative contribution of TILs to DFS was substantially greater in right- versus left-sided tumors (24% versus 1.5%). In high-risk tumors, TILs had the highest relative contribution to DFS (42%) of all variables. In low-risk tumors, the contribution of TILs (16%) to DFS was second to KRAS. CONCLUSIONS The association of TIL densities with patient survival differed by primary tumor sidedness and clinical risk group, suggesting that TILs should be interpreted in this context among stage III colon cancers. CLINICALTRIALS GOV IDENTIFIER NCT00079274; https://clinicaltrials.gov/ct2/show/NCT00079274.
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Affiliation(s)
| | - N R Foster
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester; Alliance Statistics and Data Management Center, Mayo Clinic, Rochester
| | - H E Lee
- Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester
| | - Q Shi
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester; Alliance Statistics and Data Management Center, Mayo Clinic, Rochester
| | - S R Alberts
- Division of Oncology, Mayo Clinic, Rochester, USA
| | - T C Smyrk
- Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester
| | - F A Sinicrope
- Gastrointestinal Research Unit, Mayo Clinic, Rochester; Division of Oncology, Mayo Clinic, Rochester, USA; Mayo Comprehensive Cancer Center, Rochester, MN, USA.
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23
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Martínez-Méndez D, Huerta L, Villarreal C. Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation. Front Immunol 2022; 13:962175. [PMID: 36211418 PMCID: PMC9539201 DOI: 10.3389/fimmu.2022.962175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the TFH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or TFH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression.
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Affiliation(s)
| | - Leonor Huerta
- Instituto de Investigaciones Biomédicas, Departamento de Inmunología, Universidad Nacional Autónoma de México, Mexico City, Mexico
- *Correspondence: Carlos Villarreal, ; Leonor Huerta,
| | - Carlos Villarreal
- Instituto de Física, Universidad Nacional Autónoma de México, Mexico City, Mexico
- *Correspondence: Carlos Villarreal, ; Leonor Huerta,
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24
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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25
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Iqbal H, Kim GL, Kim JH, Ghosh P, Shah M, Lee W, Rhee DK. Pneumococcal pep27-mutant inhibits Wnt5a expression via the regulation of T helper cells to attenuate colitis. Int Immunopharmacol 2022; 109:108927. [PMID: 35691272 DOI: 10.1016/j.intimp.2022.108927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 06/02/2022] [Accepted: 06/05/2022] [Indexed: 01/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic gut inflammatory disease characterized by extensive colitis and remission of the symptoms. The incidence rate and prevalence of IBD are increasing worldwide; IBD affects millions of people, has poorly defined etiology, and often results in a failure of pharmacological interventions. Regardless of the cause, mucosal healing is indispensable for the regeneration of inflamed mucosa to ensure intestinal homeostasis. Intranasal immunization with the pneumococcal pep27 mutant (Δpep27) has been reported as an avirulent and live vaccine that has been proposed to suppress immune-regulated disorders, eliciting long-lasting immunity. The dose-dependent activity of Δpep27 in the lungs was measured by transcriptome analysis to investigate the long-lasting immunogenic response against IBD. Novel therapeutic targets based on the modulation of Wnt signaling and T regulatory cells interconnected with other signaling cascades in the context of IBD were investigated by qPCR and immunoblotting. M1/M2 macrophages were quantified by FACS analysis. Dextran sulfate sodium-induced colitis induced significant upregulation of Th2 and Th17 as well as noncanonical Wnt5, which subsequently inhibited regulatory T (Treg) expression. In contrast, Δpep27 immunization significantly attenuated the levels of Wnt5, proinflammatory cytokines, oxidative stress parameters, and infiltration of inflammatory cells and enhanced barrier integrity via T helper cell homeostasis and upregulation of M2 macrophages. The data of the present study suggested that Δpep27-elicited Tregs were able to repress Wnt5a expression, assisting with the restoration of immunological tolerance and providing a robust regenerative and antioxidant milieu.
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Affiliation(s)
- Hamid Iqbal
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea
| | - Gyu-Lee Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea
| | - Ji-Hoon Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea
| | - Prachetash Ghosh
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea
| | - Masaud Shah
- Department of Physiology, Ajou University, Suwon 16499, South Korea
| | - Wonsik Lee
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea
| | - Dong-Kwon Rhee
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; DNBIO Pharm. Inc., Research Center, Suwon 16419, South Korea.
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26
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Goodla L, Xue X. The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis. Cells 2022; 11:2313. [PMID: 35954156 PMCID: PMC9367504 DOI: 10.3390/cells11152313] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal veins receiving blood from the digestive tract. Understanding the cellular and molecular mechanisms of hepatic metastases is of dire need for the development of potent targeted therapeutics. Immuno-signaling molecules including cytokines and chemokines play a pivotal role in hepatic metastases from CRC. This brief review discusses the involvement of three representative cytokines (TNF-α, IL-6 and IL-1β), a lipid molecule PGE2 and two chemokines (CXCL1 and CXCL2) in the process of CRC liver metastases.
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Affiliation(s)
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;
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27
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Aristin Revilla S, Kranenburg O, Coffer PJ. Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting. Front Immunol 2022; 13:903564. [PMID: 35874729 PMCID: PMC9304750 DOI: 10.3389/fimmu.2022.903564] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
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Affiliation(s)
- Sonia Aristin Revilla
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Onno Kranenburg
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Paul J. Coffer
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- *Correspondence: Paul J. Coffer,
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28
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Targeting interleukin-17 enhances tumor response to immune checkpoint inhibitors in colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188758. [PMID: 35809762 DOI: 10.1016/j.bbcan.2022.188758] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022]
Abstract
Although immune checkpoint inhibitors (ICIs) have gained much attention in managing cancer, only a minority of patients, especially those with tumors that have been classified as immunologically "cold" such as microsatellite stable (MSS) colorectal cancers (CRC), experience clinical benefit from ICIs. Surprisingly, interleukin-17 (IL-17) and its primary source Th17 are enriched in CRC and inversely associated with patient outcome. Our previous study revealed that IL-17A could upregulate programmed death-ligand 1 (PD-L1) expression and impede the efficacy of immunotherapy. IL-17, therefore, can be a possible target to sensitize tumor cells to ICIs. The detailed clinical results from our trial, which is the first to show the benefits of the combination of anti-PD-1 with anti-IL-17 therapy for MSS CRC, have also been presented. In this review, we highlight the role of IL-17 in ICIs resistance and summarize the current clinical evidence for the use of combination therapy. Directions for future strategies to warm up immunologically "cold" MSS CRCs have also been proposed.
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29
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Lin F, Hu X, Zhang Y, Ye S, Gu Y, Yan B, Wang L, Jiang Y. Upregulated TIGIT+ and Helios+ regulatory T cell levels in bronchoalveolar lavage fluid of NSCLC patients. Mol Immunol 2022; 147:40-49. [PMID: 35504057 DOI: 10.1016/j.molimm.2022.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/17/2022] [Accepted: 04/17/2022] [Indexed: 12/09/2022]
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30
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Obata-Ninomiya K, de Jesus Carrion S, Hu A, Ziegler SF. Emerging role for thymic stromal lymphopoietin-responsive regulatory T cells in colorectal cancer progression in humans and mice. Sci Transl Med 2022; 14:eabl6960. [PMID: 35584230 DOI: 10.1126/scitranslmed.abl6960] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. Tumor-derived factors, such as the cytokine thymic stromal lymphopoietin (TSLP), can influence Treg function in tumors. In our study, we identified a subset of Tregs expressing the receptor for TSLP (TSLPR+ Tregs) that were increased in colorectal tumors in humans and mice and largely absent in adjacent normal colon. This Treg subset was also found in the peripheral blood of patients with colon cancer but not in the peripheral blood of healthy control subjects. Mechanistically, we found that this Treg subset coexpressed the interleukin-33 (IL-33) receptor [suppressor of tumorigenicity 2 (ST2)] and had high programmed cell death 1 (PD-1) and cytotoxic lymphocyte-associated antigen 4 (CTLA-4) expression, regulated in part by the transcription factor Mef2c. Treg-specific deletion of TSLPR, but not ST2, was associated with a reduction in tumor number and size with concomitant increase in TH1 cells in tumors in chemically induced mouse models of colorectal cancer. Therapeutic blockade of TSLP using TSLP-specific monoclonal antibodies effectively inhibited the progression of colorectal tumors in this mouse model. Collectively, these data suggest that TSLP controls the progression of colorectal cancer through regulation of tumor-specific Treg function and represents a potential therapeutic target that requires further investigation.
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Affiliation(s)
| | | | - Alex Hu
- Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Steven F Ziegler
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
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31
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TCF-1: a maverick in T cell development and function. Nat Immunol 2022; 23:671-678. [PMID: 35487986 PMCID: PMC9202512 DOI: 10.1038/s41590-022-01194-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 03/22/2022] [Indexed: 02/01/2023]
Abstract
The T cell-specific DNA-binding protein TCF-1 is a central regulator of T cell development and function along multiple stages and lineages. Because it interacts with β-catenin, TCF-1 has been classically viewed as a downstream effector of canonical Wnt signaling, although there is strong evidence for β-catenin-independent TCF-1 functions. TCF-1 co-binds accessible regulatory regions containing or lacking its conserved motif and cooperates with other nuclear factors to establish context-dependent epigenetic and transcription programs that are essential for T cell development and for regulating immune responses to infection, autoimmunity and cancer. Although it has mostly been associated with positive regulation of chromatin accessibility and gene expression, TCF-1 has the potential to reduce chromatin accessibility and thereby suppress gene expression. In addition, the binding of TCF-1 bends the DNA and affects the chromatin conformation genome wide. This Review discusses the current understanding of the multiple roles of TCF-1 in T cell development and function and their mechanistic underpinnings.
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32
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Abstract
The transforming growth factor-β (TGF-β) family includes cytokines controlling cell behavior, differentiation and homeostasis of various tissues including components of the immune system. Despite well recognized importance of TGF-β in controlling T cell functions, the immunomodulatory roles of many other members of the TGF-β cytokine family, especially bone morphogenetic proteins (BMPs), start to emerge. Bone Morphogenic Protein Receptor 1α (BMPR1α) is upregulated by activated effector and Foxp3+ regulatory CD4+ T cells (Treg cells) and modulates functions of both of these cell types. BMPR1α inhibits generation of proinflammatory Th17 cells and sustains peripheral Treg cells. This finding underscores the importance of the BMPs in controlling Treg cell plasticity and transition between Treg and Th cells. BMPR1α deficiency in in vitro induced and peripheral Treg cells led to upregulation of Kdm6b (Jmjd3) demethylase, an antagonist of polycomb repressive complex 2 (PRC2), and cell cycle inhibitor Cdkn1a (p21Cip1) promoting cell senescence. This indicates that BMPs and BMPR1α may represent regulatory modules shaping epigenetic landscape and controlling proinflammatory reprogramming of Th and Treg cells. Revealing functions of other BMP receptors and their crosstalk with receptors for TGF-β will contribute to our understanding of peripheral immunoregulation.
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Affiliation(s)
- Piotr Kraj
- Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States
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33
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Masuda K, Kornberg A, Miller J, Lin S, Suek N, Botella T, Secener KA, Bacarella AM, Cheng L, Ingham M, Rosario V, Al-Mazrou AM, Lee-Kong SA, Kiran RP, Stoeckius M, Smibert P, Del Portillo A, Oberstein PE, Sims PA, Yan KS, Han A. Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer. JCI Insight 2022; 7:e154646. [PMID: 35192548 PMCID: PMC9057629 DOI: 10.1172/jci.insight.154646] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 02/16/2022] [Indexed: 01/21/2023] Open
Abstract
Clinical outcomes in colorectal cancer (CRC) correlate with T cell infiltrates, but the specific contributions of heterogenous T cell types remain unclear. To investigate the diverse function of T cells in CRC, we profiled 37,931 T cells from tumors and adjacent normal colon of 16 patients with CRC with respect to transcriptome, TCR sequence, and cell surface markers. Our analysis identified phenotypically and functionally distinguishable effector T cell types. We employed single-cell gene signatures from these T cell subsets to query the TCGA database to assess their prognostic significance. We found 2 distinct cytotoxic T cell types. GZMK+KLRG1+ cytotoxic T cells were enriched in CRC patients with good outcomes. GNLY+CD103+ cytotoxic T cells with a dysfunctional phenotype were not associated with good outcomes, despite coexpression of CD39 and CD103, markers that denote tumor reactivity. We found 2 distinct Treg subtypes associated with opposite outcomes. While total Tregs were associated with good outcomes, CD38+ Tregs were associated with bad outcomes independently of stage and possessed a highly suppressive phenotype, suggesting that they inhibit antitumor immunity in CRC. These findings highlight the potential utility of these subpopulations in predicting outcomes and support the potential for novel therapies directed at CD38+ Tregs or CD8+CD103+ T cells.
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Affiliation(s)
| | - Adam Kornberg
- Columbia Center for Translational Immunology
- Department of Microbiology & Immunology
| | - Jonathan Miller
- Department of Pediatrics
- Columbia Center for Human Development
| | - Sijie Lin
- Columbia Center for Translational Immunology
| | - Nathan Suek
- Columbia Center for Translational Immunology
| | | | | | | | | | - Matthew Ingham
- Department of Medicine, Division of Hematology & Oncology
- Herbert Irving Comprehensive Cancer Center, and
| | - Vilma Rosario
- Herbert Irving Comprehensive Cancer Center, and
- Department of Surgery, Division of Colorectal Surgery, Columbia University, New York, New York, USA
| | - Ahmed M. Al-Mazrou
- Herbert Irving Comprehensive Cancer Center, and
- Department of Surgery, Division of Colorectal Surgery, Columbia University, New York, New York, USA
| | - Steven A. Lee-Kong
- Herbert Irving Comprehensive Cancer Center, and
- Department of Surgery, Division of Colorectal Surgery, Columbia University, New York, New York, USA
| | - Ravi P. Kiran
- Herbert Irving Comprehensive Cancer Center, and
- Department of Surgery, Division of Colorectal Surgery, Columbia University, New York, New York, USA
| | | | | | | | - Paul E. Oberstein
- Department of Medicine, Division of Hematology & Oncology
- Herbert Irving Comprehensive Cancer Center, and
| | - Peter A. Sims
- Departments of Systems Biology and Biochemistry & Molecular Biophysics
| | - Kelley S. Yan
- Columbia Center for Human Development
- Department of Medicine, Division of Digestive & Liver Diseases, and
- Department of Genetics & Development, Columbia University, New York, New York, USA
| | - Arnold Han
- Columbia Center for Translational Immunology
- Department of Microbiology & Immunology
- Herbert Irving Comprehensive Cancer Center, and
- Department of Medicine, Division of Digestive & Liver Diseases, and
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Dean JW, Zhou L. Cell-intrinsic view of the aryl hydrocarbon receptor in tumor immunity. Trends Immunol 2022; 43:245-258. [PMID: 35131180 PMCID: PMC8882133 DOI: 10.1016/j.it.2022.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/15/2022]
Abstract
Emerging insights into aryl hydrocarbon receptor (Ahr) biology have revealed its key role in regulating mammalian host immunity and tissue homeostasis. Depending on the context, immune cells can play either a pro- or antitumor role in cancer. Ahr has classically been viewed as protumorigenic; however, given recent advances in our understanding of Ahr functions, especially in the immune system, this view requires reassessment. Moreover, given its cell type-specific activity, therapeutic exploitation of the Ahr pathway should be cautiously considered. We describe the function of Ahr in different immune cells, and connect with their roles in cancer immunology. In addition, we discuss clinical perspectives of how recent advances in our understanding of Ahr biology might be therapeutically applied to improve cancer outcomes.
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Affiliation(s)
- Joseph W. Dean
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Liang Zhou
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA.
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35
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Bandaru SS, Boyilla R, Merchant N, Nagaraju GP, El-Rayes B. Targeting T regulatory cells: their role in colorectal carcinoma progression and current clinical trials. Pharmacol Res 2022; 178:106197. [DOI: 10.1016/j.phrs.2022.106197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 10/18/2022]
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Yang R, Qian L. Research on Gut Microbiota-Derived Secondary Bile Acids in Cancer Progression. Integr Cancer Ther 2022; 21:15347354221114100. [PMID: 35880833 PMCID: PMC9421216 DOI: 10.1177/15347354221114100] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The interaction between gut microbiota-derived metabolites and the body plays a
significant role in the occurrence and development of cancer. Secondary bile
acids (BAs) are the important products produced from gut microbial fermentation
of primary BAs, mainly deoxycholic acid (DCA) and lithocholic acid (LCA). In the
gut, they can influence the structure of the microbial communities. Several
studies have demonstrated that secondary BAs, as signaling molecules, can
activate a variety of signaling pathways. They can inhibit the apoptosis of
cancer cells, induce the progression of cancer cell cycles, enhance the ability
of metastasis and invasion of cancer cells, and promote the transformation of
cells into cancer stem cells (CSCs). Moreover, secondary BAs promote cancer by
regulating the function of immune cells. Therefore, targeted manipulation of gut
microbial and secondary BAs has the potential to be developed as for treatment
and prevention of various cancers.
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Affiliation(s)
- Rong Yang
- Medical College, Yangzhou University, Yangzhou, China
| | - Li Qian
- Medical College, Yangzhou University, Yangzhou, China
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37
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Li Y, Li Y, Xia Z, Zhang D, Chen X, Wang X, Liao J, Yi W, Chen J. Identification of a novel immune signature for optimizing prognosis and treatment prediction in colorectal cancer. Aging (Albany NY) 2021; 13:25518-25549. [PMID: 34898475 PMCID: PMC8714135 DOI: 10.18632/aging.203771] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/22/2021] [Indexed: 04/11/2023]
Abstract
BACKGROUND Globally, colorectal cancer (CRC) is one of the most lethal malignant diseases. However, the currently approved therapeutic options for CRC failed to acquire satisfactory treatment efficacy. Tailoring therapeutic strategies for CRC individuals can provide new insights into personalized prediction approaches and thus maximize clinical benefits. METHODS In this study, a multi-step process was used to construct an immune-related genes (IRGs) based signature leveraging the expression profiles and clinical characteristics of CRC from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. An integrated immunogenomic analysis was performed to determine the association between IRGs with prognostic significance and cancer genotypes in the tumor immune microenvironment (TIME). Moreover, we performed a comprehensive in silico therapeutics screening to identify agents with subclass-specific efficacy. RESULTS The established signature was shown to be a promising biomarker for evaluating clinical outcomes in CRC. The immune risk score as calculated by this classifier was significantly correlated with over-riding malignant phenotypes and immunophenotypes. Further analyses demonstrated that CRCs with low immune risk scores achieved better therapeutic benefits from immunotherapy, while AZD4547, Cytochalasin B and S-crizotinib might have potential therapeutic implications in the immune risk score-high CRCs. CONCLUSIONS Overall, this IRGs-based signature not only afforded a useful tool for determining the prognosis and evaluating the TIME features of CRCs, but also shed new light on tailoring CRCs with precise treatment.
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Affiliation(s)
- Yan Li
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yiyi Li
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zijin Xia
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Dun Zhang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaomei Chen
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinyu Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jing Liao
- The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wei Yi
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jun Chen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Engineering and Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Center for Precision Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
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38
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Lücke J, Shiri AM, Zhang T, Kempski J, Giannou AD, Huber S. Rationalizing heptadecaphobia: T H 17 cells and associated cytokines in cancer and metastasis. FEBS J 2021; 288:6942-6971. [PMID: 33448148 DOI: 10.1111/febs.15711] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/13/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022]
Abstract
Cancer is one of the leading causes of death worldwide. When cancer patients are diagnosed with metastasis, meaning that the primary tumor has spread to at least one different site, their life expectancy decreases dramatically. In the past decade, the immune system´s role in fighting cancer and metastasis has been studied extensively. Importantly, immune cells and inflammatory reactions generate potent antitumor responses but also contribute to tumor development. However, the molecular and cellular mechanisms underlying this dichotomic interaction between the immune system and cancer are still poorly understood. Recently, a spotlight has been cast on the distinct subsets of immune cells and their derived cytokines since evidence has implicated their crucial impact on cancer development. T helper 17 cell (TH 17) cells, which express the master transcriptional factor Retinoic acid-receptor-related orphan receptor gamma t, are among these critical cell subsets and are defined by their production of type 3 cytokines, such as IL-17A, IL-17F, and IL-22. Depending on the tumor microenvironment, these cytokines can also be produced by other immune cell sources, such as T cytotoxic 17 cell, innate lymphoid cells, NKT cells, or γδ T cells. To date, a lot of data have been collected describing the divergent functions of IL-17A, IL-17F, and IL-22 in malignancies. In this comprehensive review, we discuss the role of these TH 17- and non-TH 17-derived type 3 cytokines in different tumor entities. Furthermore, we will provide a structured insight into the strict regulation and subsequent downstream mechanisms of these cytokines in cancer and metastasis.
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Affiliation(s)
- Jöran Lücke
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Ahmad Mustafa Shiri
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Tao Zhang
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Jan Kempski
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
- The Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Germany
| | - Anastasios D Giannou
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Germany
| | - Samuel Huber
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
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39
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Bernard-Raichon L, Colom A, Monard SC, Namouchi A, Cescato M, Garnier H, Leon-Icaza SA, Métais A, Dumas A, Corral D, Ghebrendrias N, Guilloton P, Vérollet C, Hudrisier D, Remot A, Langella P, Thomas M, Cougoule C, Neyrolles O, Lugo-Villarino G. A Pulmonary Lactobacillus murinus Strain Induces Th17 and RORγt + Regulatory T Cells and Reduces Lung Inflammation in Tuberculosis. THE JOURNAL OF IMMUNOLOGY 2021; 207:1857-1870. [PMID: 34479945 DOI: 10.4049/jimmunol.2001044] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 07/24/2021] [Indexed: 12/31/2022]
Abstract
The lungs harbor multiple resident microbial communities, otherwise known as the microbiota. There is an emerging interest in deciphering whether the pulmonary microbiota modulate local immunity, and whether this knowledge could shed light on mechanisms operating in the response to respiratory pathogens. In this study, we investigate the capacity of a pulmonary Lactobacillus strain to modulate the lung T cell compartment and assess its prophylactic potential upon infection with Mycobacterium tuberculosis, the etiological agent of tuberculosis. In naive mice, we report that a Lactobacillus murinus (Lagilactobacillus murinus) strain (CNCM I-5314) increases the presence of lung Th17 cells and of a regulatory T cell (Treg) subset known as RORγt+ Tregs. In particular, intranasal but not intragastric administration of CNCM I-5314 increases the expansion of these lung leukocytes, suggesting a local rather than systemic effect. Resident Th17 and RORγt+ Tregs display an immunosuppressive phenotype that is accentuated by CNCM I-5314. Despite the well-known ability of M. tuberculosis to modulate lung immunity, the immunomodulatory effect by CNCM I-5314 is dominant, as Th17 and RORγt+ Tregs are still highly increased in the lung at 42-d postinfection. Importantly, CNCM I-5314 administration in M. tuberculosis-infected mice results in reduction of pulmonary inflammation, without increasing M. tuberculosis burden. Collectively, our findings provide evidence for an immunomodulatory capacity of CNCM I-5314 at steady state and in a model of chronic inflammation in which it can display a protective role, suggesting that L. murinus strains found in the lung may shape local T cells in mice and, perhaps, in humans.
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Affiliation(s)
- Lucie Bernard-Raichon
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France;
| | - André Colom
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Sarah C Monard
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Amine Namouchi
- Centre for Integrative Genetics, Norwegian University of Life Sciences, As, Norway; and
| | - Margaux Cescato
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Hugo Garnier
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Stephen A Leon-Icaza
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Arnaud Métais
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Alexia Dumas
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Dan Corral
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Natsinet Ghebrendrias
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Pauline Guilloton
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Christel Vérollet
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Denis Hudrisier
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Aude Remot
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Philippe Langella
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Muriel Thomas
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Céline Cougoule
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Olivier Neyrolles
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Geanncarlo Lugo-Villarino
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France;
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40
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Yu W, Ji N, Gu C, Yao J, Ding M, Zhou D, Huang M, Zhang M. IRF4 is Correlated with the Conversion to a Th17-Like Phenotype in Regulatory T Cells from the Malignant Pleural Effusion. Int J Gen Med 2021; 14:6009-6019. [PMID: 34588805 PMCID: PMC8476179 DOI: 10.2147/ijgm.s330389] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/13/2021] [Indexed: 11/23/2022] Open
Abstract
Background RORγt+Foxp3+ (Th17-like) Tregs are a plastic Treg subset implicated in immune-related diseases; however, the mechanism of Treg phenotypic transformation in malignant pleural effusion (MPE) has not been elucidated. Methods The percentage of CD4+CD25+Foxp3+Helios+ and RORγt+Foxp3+ Tregs from peripheral blood and pleural effusion mononuclear cells were measured. The level of interferon regulatory factor 4 (IRF4) mRNA expression was detected by quantitative real-time reverse transcription polymerase chain reaction. The effects of IRF4 on the induction of Tregs from patients with non-small cell lung cancer (NSCLC) were evaluated in vitro. Correlation assays between IRF4 expression and the frequency of RORγt+Foxp3+ Tregs were performed. Results The frequency of CD4+CD25+Foxp3+Helios+ Tregs and CD4+RORγt+ Th17 cells was both increased in the MPE of NSCLC patients. The group of double-positive Foxp3+RORγt+ Treg phenotype were identified in the pleural effusion. A significant increase in the frequency of Foxp3+RORγt+ Tregs was found in MPE compared with the non-malignant pleural effusion (NPE). Compared to NPE, the relative level of IRF4 expression was increased in the MPE. IRF4 expression was positively associated with the frequency of Foxp3+RORγt+ Tregs in the PE. In vitro, the level of Helios mRNA and protein expression was reduced in induced Tregs following IRF4 over-expression. Additionally, the level of RORγt protein expression was substantially increased. However, ectopic Helios expression in induced Tregs reversed the effects induced by enhanced IRF4 expression. Conclusion IRF4 may serve as a potential molecule that promotes the conversion of regulatory T cells from MPE to a Th17-like phenotype by modulating Helios.
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Affiliation(s)
- Wenqing Yu
- Department of Infectious Diseases, Taizhou People's Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People's Republic of China
| | - Ningfei Ji
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Chengjing Gu
- Department of Pharmacy, Taizhou People's Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People's Republic of China
| | - Juan Yao
- Department of Oncology, Huaian Hospital of Huaian City, Huaian, Jiangsu, 223200, People's Republic of China
| | - Mingdong Ding
- Department of Infectious Diseases, Taizhou People's Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People's Republic of China
| | - Daming Zhou
- Department of Infectious Diseases, Taizhou People's Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People's Republic of China
| | - Mao Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Mingshun Zhang
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, People's Republic of China.,NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, 211166, People's Republic of China
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41
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Chao JL, Korzinkin M, Zhavoronkov A, Ozerov IV, Walker MT, Higgins K, Lingen MW, Izumchenko E, Savage PA. Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma. Cell Rep Med 2021; 2:100399. [PMID: 34622236 PMCID: PMC8484691 DOI: 10.1016/j.xcrm.2021.100399] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/08/2021] [Accepted: 08/23/2021] [Indexed: 12/16/2022]
Abstract
Immune suppression by CD4+FOXP3+ regulatory T (Treg) cells and tumor infiltration by CD8+ effector T cells represent two major factors impacting response to cancer immunotherapy. Using deconvolution-based transcriptional profiling of human papilloma virus (HPV)-negative oral squamous cell carcinomas (OSCCs) and other solid cancers, we demonstrate that the density of Treg cells does not correlate with that of CD8+ T cells in many tumors, revealing polarized clusters enriched for either CD8+ T cells or CD4+ Treg and conventional T cells. In a mouse model of carcinogen-induced OSCC characterized by CD4+ T cell enrichment, late-stage Treg cell ablation triggers increased densities of both CD4+ and CD8+ effector T cells within oral lesions. Notably, this intervention does not induce tumor regression but instead induces rapid emergence of invasive OSCCs via an effector T cell-dependent process. Thus, induction of a T cell-inflamed phenotype via therapeutic manipulation of Treg cells may trigger unexpected tumor-promoting effects in OSCC.
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Affiliation(s)
- Jaime L. Chao
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | | | | | - Ivan V. Ozerov
- Insilico Medicine Hong Kong, Ltd., Pak Shek Kok, Hong Kong
| | - Matthew T. Walker
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Kathleen Higgins
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Mark W. Lingen
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Evgeny Izumchenko
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Peter A. Savage
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
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42
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Browning LM, Miller C, Kuczma M, Pietrzak M, Jing Y, Rempala G, Muranski P, Ignatowicz L, Kraj P. Bone Morphogenic Proteins Are Immunoregulatory Cytokines Controlling FOXP3 + T reg Cells. Cell Rep 2021; 33:108219. [PMID: 33027660 DOI: 10.1016/j.celrep.2020.108219] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 07/28/2020] [Accepted: 09/10/2020] [Indexed: 12/23/2022] Open
Abstract
Bone morphogenic proteins (BMPs) are members of the transforming growth factor β (TGF-β) cytokine family promoting differentiation, homeostasis, and self-renewal of multiple tissues. We show that signaling through the bone morphogenic protein receptor 1α (BMPR1α) sustains expression of FOXP3 in Treg cells in peripheral lymphoid tissues. BMPR1α signaling promotes molecular circuits supporting acquisition and preservation of Treg cell phenotype and inhibiting differentiation of pro-inflammatory effector Th1/Th17 CD4+ T cell. Mechanistically, increased expression of KDM6B (JMJD3) histone demethylase, an antagonist of the polycomb repressive complex 2, underlies lineage-specific changes of T cell phenotypes associated with abrogation of BMPR1α signaling. These results reveal that BMPs are immunoregulatory cytokines mediating maturation and stability of peripheral FOXP3+ regulatory T cells (Treg cells) and controlling generation of iTreg cells. Thus, we establish that BMPs, a large cytokine family, are an essential link between stromal tissues and the adaptive immune system involved in sustaining tissue homeostasis by promoting immunological tolerance.
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Affiliation(s)
- Lauren M Browning
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA
| | - Caroline Miller
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA
| | - Michal Kuczma
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
| | - Maciej Pietrzak
- Department of Biomedical Informatics, Ohio State University, Columbus, OH 43210, USA
| | - Yu Jing
- Center for Bioelectrics, Old Dominion University, Norfolk, VA 23529, USA
| | - Grzegorz Rempala
- College of Public Health, Ohio State University, Columbus, OH 43210, USA
| | - Pawel Muranski
- Columbia University Medical Center, New York, NY 10032, USA
| | - Leszek Ignatowicz
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
| | - Piotr Kraj
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA.
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43
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DiToro D, Basu R. Emerging Complexity in CD4 +T Lineage Programming and Its Implications in Colorectal Cancer. Front Immunol 2021; 12:694833. [PMID: 34489941 PMCID: PMC8417887 DOI: 10.3389/fimmu.2021.694833] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/04/2021] [Indexed: 12/17/2022] Open
Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
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Affiliation(s)
- Daniel DiToro
- Brigham and Women's Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,Ragon Institute of MGH MIT and Harvard, Cambridge, MA, United States
| | - Rajatava Basu
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
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44
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Chen YH, Lightman S, Calder VL. CD4 + T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease. Int J Mol Sci 2021; 22:9584. [PMID: 34502490 PMCID: PMC8431487 DOI: 10.3390/ijms22179584] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 01/14/2023] Open
Abstract
Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these 'plastic CD4+ T cells' are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.
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Affiliation(s)
- Yi-Hsing Chen
- UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; (Y.-H.C.); (S.L.)
- Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Sue Lightman
- UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; (Y.-H.C.); (S.L.)
| | - Virginia L. Calder
- UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; (Y.-H.C.); (S.L.)
- NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK
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TCF-1 controls T reg cell functions that regulate inflammation, CD8 + T cell cytotoxicity and severity of colon cancer. Nat Immunol 2021; 22:1152-1162. [PMID: 34385712 PMCID: PMC8428683 DOI: 10.1038/s41590-021-00987-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.
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Ocvirk S, O'Keefe SJD. Dietary fat, bile acid metabolism and colorectal cancer. Semin Cancer Biol 2021; 73:347-355. [PMID: 33069873 DOI: 10.1016/j.semcancer.2020.10.003] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) risk is predominantly driven by environmental factors, in particular diet. A high intake of dietary fat has been implicated as a risk factor inducing the formation of pre-neoplastic lesions (e.g., adenomatous polyps) and/or exacerbating colonic tumorigenesis. Recent data attributed the tumor-promoting activity of high-fat diets to their effects on gut microbiota composition and metabolism, in particular with regard to bile acids. Bile acids are synthesized in the liver in response to dietary fat and facilitate lipid absorption in the small intestine. The majority of bile acids is re-absorbed during small intestinal transit and subjected to enterohepatic circulation. Bile acids entering the colon undergo complex biotransformation performed by gut bacteria, resulting in secondary bile acids that show tumor-promoting activity. Excessive dietary fat leads to high levels of secondary bile acids in feces and primes the gut microbiota to bile acid metabolism. This promotes an altered overall bile acid pool, which activates or restricts intestinal and hepatic cross-signaling of the bile acid receptor, farnesoid X receptor (FXR). Recent studies provided evidence that FXR is a main regulator of bile acid-mediated effects on intestinal tumorigenesis integrating dietary, microbial and genetic risk factors for CRC. Selective FXR agonist or antagonist activity by specific bile acids depends on additional factors (e.g., bile acid concentration, composition of bile acid pool, genetic instability of cells) and, thus, may differ in healthy and tumorigenic conditions in the intestine. In conclusion, fat-mediated alterations of the gut microbiota link bile acid metabolism to CRC risk and colonic tumorigenesis, exemplifying how gut microbial co-metabolism affects colon health.
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Affiliation(s)
- Soeren Ocvirk
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Intestinal Microbiology Research Group, Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
| | - Stephen J D O'Keefe
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Lu Y, Li Y, Liu Q, Tian N, Du P, Zhu F, Han Y, Liu X, Liu X, Peng X, Wang X, Wu Y, Tong L, Li Y, Zhu Y, Wu L, Zhang P, Xu Y, Chen H, Li B, Tong X. MondoA-Thioredoxin-Interacting Protein Axis Maintains Regulatory T-Cell Identity and Function in Colorectal Cancer Microenvironment. Gastroenterology 2021; 161:575-591.e16. [PMID: 33901495 DOI: 10.1053/j.gastro.2021.04.041] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 04/15/2021] [Accepted: 04/15/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS The metabolic features and function of intratumoral regulatory T cells (Tregs) are ambiguous in colorectal cancer. Tumor-infiltrating Tregs are reprogrammed to exhibit high glucose-depleting properties and adapt to the glucose-restricted microenvironment. The glucose-responsive transcription factor MondoA is highly expressed in Tregs. However, the role of MondoA in colorectal cancer-infiltrating Tregs in response to glucose limitation remains to be elucidated. METHODS We performed studies using mice, in which MondoA was conditionally deleted in Tregs, and human colorectal cancer tissues. Seahorse and other metabolic assays were used to assess Treg metabolism. To study the role of Tregs in antitumor immunity, we used a subcutaneous MC38 colorectal cancer model and induced colitis-associated colorectal cancer in mice by azoxymethane and dextran sodium sulfate. RESULTS Our analysis of single-cell RNA sequencing data of patients with colorectal cancer revealed that intratumoral Tregs featured low activity of the MondoA-thioredoxin-interacting protein (TXNIP) axis and increased glucose uptake. Although MondoA-deficient Tregs were less immune suppressive and selectively promoted T-helper (Th) cell type 1 (Th1) responses in a subcutaneous MC38 tumor model, Treg-specific MondoA knockout mice were more susceptible to azoxymethane-DSS-induced colorectal cancer. Mechanistically, suppression of the MondoA-TXNIP axis promoted glucose uptake and glycolysis, induced hyperglycolytic Th17-like Tregs, which facilitated Th17 inflammation, promoted interleukin 17A-induced of CD8+ T-cell exhaustion, and drove colorectal carcinogenesis. Blockade of interleukin 17A reduced tumor progression and minimized the susceptibility of MondoA-deficient mice to colorectal carcinogenesis. CONCLUSIONS The MondoA-TXNIP axis is a critical metabolic regulator of Treg identity and function in the colorectal cancer microenvironment and a promising target for cancer therapy.
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Affiliation(s)
- Ying Lu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangyang Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qi Liu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Na Tian
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangming Zhu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yichao Han
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinnan Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xisheng Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Peng
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxia Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuchen Wu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lingfeng Tong
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yakui Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yemin Zhu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lifang Wu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Zhang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hanbei Chen
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Bin Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Henan Key Laboratory for Digestive Organ Transplantation, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China.
| | - Xuemei Tong
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Affiliation(s)
- Stefania Canè
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
| | - Vincenzo Bronte
- Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
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Hibino S, Kawazoe T, Kasahara H, Itoh S, Ishimoto T, Sakata-Yanagimoto M, Taniguchi K. Inflammation-Induced Tumorigenesis and Metastasis. Int J Mol Sci 2021; 22:ijms22115421. [PMID: 34063828 PMCID: PMC8196678 DOI: 10.3390/ijms22115421] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
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Affiliation(s)
- Sana Hibino
- Research Center for Advanced Science and Technology, Department of Inflammology, The University of Tokyo, Tokyo 153-0041, Japan;
| | - Tetsuro Kawazoe
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Hidenori Kasahara
- National Center for Global Health and Medicine, Department of Stem Cell Biology, Research Institute, Tokyo 162-8655, Japan;
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Takatsugu Ishimoto
- Gastrointestinal Cancer Biology, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan;
| | | | - Koji Taniguchi
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Correspondence: ; Tel.: +81-11-706-5050
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Fantini MC, Guadagni I. From inflammation to colitis-associated colorectal cancer in inflammatory bowel disease: Pathogenesis and impact of current therapies. Dig Liver Dis 2021; 53:558-565. [PMID: 33541800 DOI: 10.1016/j.dld.2021.01.012] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/23/2020] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
The risk of colorectal cancer (CRC) is higher in patients with inflammatory bowel disease (IBD). Population-based data from patients with ulcerative colitis (UC) estimate that the risk of CRC is approximately 2- to 3-fold that of the general population; patients with Crohn's disease appear to have a similar increased risk. However, the true extent of colitis-associated cancer (CAC) in undertreated IBD is unclear. Data suggest that the size (i.e., severity and extent) and persistence of the inflammatory process is largely responsible for the development of CRC in IBD. As patients with IBD and CRC have a worse prognosis than those without a history of IBD, the impact of current therapies for IBD on CAC is of importance. Chronic inflammation of the gut has been shown to increase the risk of developing CAC in both UC and CD. Therefore, control of inflammation is pivotal to the prevention of CAC. This review presents an overview of the current knowledge of CAC in IBD patients, focusing on the role of inflammation in the pathogenesis of CAC and the potential for IBD drugs to interfere with the process of carcinogenesis by reducing the inflammatory process or by modulating pathways directly involved in carcinogenesis.
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Affiliation(s)
- Massimo Claudio Fantini
- Department of Medical Science and Public Health, Gastroenterology Unit, University of Cagliari, Cittadella Universitaria di Monserrato - Asse Didattico I, SS 554 bivio Sestu, 09042 Monserrato, Cagliari, Italy.
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