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Zhang X, Li B, Lan T, Chiari C, Ye X, Wang K, Chen J. The role of interleukin-17 in inflammation-related cancers. Front Immunol 2025; 15:1479505. [PMID: 39906741 PMCID: PMC11790576 DOI: 10.3389/fimmu.2024.1479505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/27/2024] [Indexed: 02/06/2025] Open
Abstract
Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity in several models of grafted subcutaneous tumors. Additionally, dynamic changes in the microbiome can influence the secretion of IL-17, thereby affecting tumor development. The specific role of IL-17 is contingent upon its functional classification, spatiotemporal characteristics, and the stage of tumor development. In this review, we introduce the fundamental biology of IL-17 and the expression profile of its receptors in cancer, while also reviewing and discussing recent advancements regarding the pleiotropic effects and mechanisms of IL-17 in inflammation-related cancers. Furthermore, we supplement our discussion with insights into the mechanisms by which IL-17 impacts cancer progression through interactions with the microbiota, and we explore the implications of IL-17 in cancer therapy. This comprehensive analysis aims to enhance our understanding of IL-17 and its potential role in cancer treatment.
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Affiliation(s)
- Xingru Zhang
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Bangjie Li
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
| | - Tian Lan
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Conner Chiari
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Xiaoyang Ye
- College of Engineering, Northeastern University, Seattle, WA, United States
| | - Kepeng Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Ju Chen
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
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Begagic E, Vranic S, Sominanda A. The role of interleukin 17 in cancer: a systematic review. Carcinogenesis 2025; 46:bgae079. [PMID: 39673782 DOI: 10.1093/carcin/bgae079] [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: 09/07/2024] [Revised: 12/08/2024] [Accepted: 12/13/2024] [Indexed: 12/16/2024] Open
Abstract
Interleukin 17 (IL17) is a cytokine involved in immune regulation and has been increasingly recognized for its role in cancer progression. This systematic review aims to integrate data on IL17's role in various tumors to better understand its implications for cancer prognosis and treatment. The review included 105 studies (27.6% experimental and 72.4% clinical). Clinical studies involved 9266 patients: 31.2% males, 60.0% females, and 8.8% with undefined gender. IL17A and IL17 were the most studied subtypes (36.2% and 33.3%, respectively). Breast cancer (26.7%), colorectal carcinoma (13.3%), and hematologic malignancies (10.5%) were the most researched neoplasms. IL17A promoted tumor growth in breast cancer and correlated with poor outcomes in colorectal, breast, and lung cancers. IL17 also played a significant role in immune modulation in gliomas and other tumors. IL17A significantly influences tumor growth and prognosis across various cancers, with notable roles in immune modulation and poor outcomes in multiple cancer types.
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Affiliation(s)
- Emir Begagic
- Department of Neurosurgery, Cantonal Hospital Zenica, Crkvice 67, 72000 Zenica, Bosnia and Herzegovina
| | - Semir Vranic
- Department of Pathology, College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ajith Sominanda
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
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Yang ZX, Zhang LT, Liu XJ, Peng XB, Mao XR. Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:97831. [PMID: 39817127 PMCID: PMC11664623 DOI: 10.4251/wjgo.v17.i1.97831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/02/2024] [Accepted: 10/28/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC. AIM To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC. METHODS The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo. RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model. CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
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Affiliation(s)
- Zhong-Xia Yang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Li-Ting Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Liu
- Department of Radiotherapy, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xue-Bin Peng
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Rong Mao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Ying S, Wu N, Ruan Y, Ge W, Ma P, Xu T, Shu Y, Wang Y, Qiu W, Zhao C. IL-17 triggers PD-L1 gene transcription in NSCLC cells via TRIM31-dependent MEF2C K63-linked polyubiquitination. BMC Cancer 2025; 25:81. [PMID: 39810133 PMCID: PMC11731414 DOI: 10.1186/s12885-025-13473-w] [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: 08/20/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is a disease related to inflammation. Proinflammatory cytokines such as interleukin 17 (IL-17) can induce cancer cell proliferation, metastasis and immune escape. Although NSCLC immune escape is partly due to the interaction between PD-1 and PD-L1 and PD-L1 expression can be upregulated in cancer cells upon stimulation with IL-17, the underlying mechanism of IL-17-triggered PD-L1 gene transcription in NSCLC cells remains elusive. METHODS RT‒PCR, real-time PCR, and IB were used to assess the levels of PD-L1, MEF2C, and TRIM31 in NSCLC tissues as well as in IL-17-stimulated H1299 or PC9 cells. Bioinformatics analysis, luciferase assays, and ChIP were utilized to investigate the transcriptional mechanism of the PD-L1 gene. Co-IP/IB was used to examine the interaction between MEF2C and PD-L1, including MEF2C ubiquitination. IHC staining was carried out to analyse the expression of IL-17RA, MEF2C, TRIM31, and PD-L1 in NSCLC tissue arrays. The corresponding plasmids were constructed and identified. An isograft model was used to verify the findings in vitro. RESULTS PD-L1, MEF2C and TRIM31 expression levels were increased in NSCLC tissues and NSCLC cells exposed to IL-17. Mechanistically, MEF2C could bind to the - 778 to -475 nt and - 336 to -97 nt regions of the PD-L1 promoter. TRIM31 could mediate MEF2C K63-linked polyubiquitination at Lys 25, increasing MEF2C recruitment to the PD-L1 promoter and PD-L1 gene transcription. MEF2C, TRIM31 or PD-L1 gene silencing effectively suppressed MEF2C K63-linked polyubiquitination, PD-L1 induction and NSCLC growth in mice inoculated with Lewis lung cancer (LLC) cells transfected with the corresponding shRNA and treated with IL-17. CONCLUSION IL-17 induces PD-L1 gene transcription in NSCLC cells through TRIM31-dependent MEF2C K63-linked polyubiquitination.
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Affiliation(s)
- Shuai Ying
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
- Department of Laboratory Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Ningxia Wu
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
- Department of Blood Transfusion, Nanjing Tianyinshan Hospital of China Pharmaceutical University, Nanjing, 211800, China
| | - Yuting Ruan
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
| | - Wen Ge
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
| | - Pei Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Tongpeng Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Yingwei Wang
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
| | - Wen Qiu
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, China
| | - Chenhui Zhao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China.
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Luo X, Lv Y, Yang J, Long R, Qiu J, Deng Y, Tang G, Zhang C, Li J, Zuo J. Gamma delta T cells in cancer therapy: from tumor recognition to novel treatments. Front Med (Lausanne) 2024; 11:1480191. [PMID: 39748921 PMCID: PMC11693687 DOI: 10.3389/fmed.2024.1480191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025] Open
Abstract
Traditional immunotherapies mainly focus on αβ T cell-based strategies, which depend on MHC-mediated antigen recognition. However, this approach poses significant challenges in treating recurrent tumors, as immune escape mechanisms are widespread. γδ T cells, with their ability for MHC-independent antigen presentation, offer a promising alternative that could potentially overcome limitations observed in traditional immunotherapies. These cells play a role in tumor immune surveillance through a unique mechanism of antigen recognition and synergistic interactions with other immune effector cells. In this review, we will discuss the biological properties of the Vδ1 and Vδ2 T subsets of γδ T cells, their immunomodulatory role within the tumor microenvironment, and the most recent clinical advances in γδ T cell-based related immunotherapies, including cell engaging strategies and adoptive cell therapy.
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Affiliation(s)
- Xinyu Luo
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Yufan Lv
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Jinsai Yang
- Computer Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Rou Long
- Transformation Research Lab, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jieya Qiu
- Transformation Research Lab, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuqi Deng
- Transformation Research Lab, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Guiyang Tang
- Transformation Research Lab, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Chaohui Zhang
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Jiale Li
- Computer Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jianhong Zuo
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Computer Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Transformation Research Lab, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- The Third Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
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Ullah A, Chen Y, Singla RK, Cao D, Shen B. Pro-inflammatory cytokines and CXC chemokines as game-changer in age-associated prostate cancer and ovarian cancer: Insights from preclinical and clinical studies' outcomes. Pharmacol Res 2024; 204:107213. [PMID: 38750677 DOI: 10.1016/j.phrs.2024.107213] [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: 01/29/2024] [Revised: 04/15/2024] [Accepted: 05/09/2024] [Indexed: 06/01/2024]
Abstract
Prostate cancer (PC) and Ovarian cancer (OC) are two of the most common types of cancer that affect the reproductive systems of older men and women. These cancers are associated with a poor quality of life among the aged population. Therefore, finding new and innovative ways to detect, treat, and prevent these cancers in older patients is essential. Finding biomarkers for these malignancies will increase the chance of early detection and effective treatment, subsequently improving the survival rate. Studies have shown that the prevalence and health of some illnesses are linked to an impaired immune system. However, the age-associated changes in the immune system during malignancies such as PC and OC are poorly understood. Recent research has suggested that the excessive production of inflammatory immune mediators, such as interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor (TGF), tumor necrosis factor (TNF), CXC motif chemokine ligand 1 (CXCL1), CXC motif chemokine ligand 12 (CXCL12), and CXC motif chemokine ligand 13 (CXCL13), etc., significantly impact the development of PC and OC in elderly patients. Our review focuses on the latest functional studies of pro-inflammatory cytokines (interleukins) and CXC chemokines, which serve as biomarkers in elderly patients with PC and OC. Thus, we aim to shed light on how these biomarkers affect the development of PC and OC in elderly patients. We also examine the current status and future perspective of cytokines (interleukins) and CXC chemokines-based therapeutic targets in OC and PC treatment for elderly patients.
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Affiliation(s)
- Amin Ullah
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yongxiu Chen
- Gynecology Department, Guangdong Women and Children Hospital, No. 521, Xingnan Road, Panyu District, Guangzhou 511442, China
| | - Rajeev K Singla
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bairong Shen
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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Dong S, Wang P, Zhang L, Zhang X, Li X, Wang J, Cui X, Lan T, Gao C, Shi Y, Wang W, Wang J, Jiang M. The Qi Yin San Liang San decoction enhances anti-CD19 CAR-T cell function in the treatment of B-cell lymphomas. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117109. [PMID: 37657771 DOI: 10.1016/j.jep.2023.117109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/17/2023] [Accepted: 08/29/2023] [Indexed: 09/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)-expressing T cells is a new approach for treating advanced B-cell malignancies. However, CAR-Tcell therapies for tumors are challenging due to tumor heterogeneity, cytokine release syndrome (CRS), and CAR-T cell exhaustion. The Qi Yin San Liang San (SLS) decoction has a significant curative effect in treating tumors and can improve clinical efficacy when combined with tumor immunotherapy. However, there has been no in vitro or in vivo pharmacodynamic evaluation of SLS in combination with immunotherapy, and the underlying immunological mechanism remains unclear. AIM OF THE REVIEW The study objective was to determine the auxiliary effect and potential mechanism of SLS as an adjuvant treatment with anti-CD19 CAR-T cells for B-cell lymphomas. MATERIALS AND METHODS Network pharmacology analyses, in vitro and in vivo studies, and transcriptome sequencing analyses were performed. RESULTS Forty-two components were detected in SLS by HPLC. Sixteen pharmacologically active ingredients were analyzed by searching the TCMSP database. The predicted targets included IL-2, IL-6, IL-10, TNF-α, CASP7, and CASP9. In vitro studies revealed that SLS can dose-dependently promote the killing effect of unmodified T and anti-CD19 CAR-T cells against Raji cell lines. Meanwhile, SLS inhibited unmodified T and anti-CD19 CAR-T cell exhaustion, promoted anti-CD19 CAR-T cell proliferation, reduced the levels of IL-6, IL-10, and TNF-α, and increased granzyme B levels. In vivo studies, SLS effectively improved the anti-tumor function of anti-CD19 CAR-T cells, prolonged the survival of the mice, and reduced the levels of IL-6, GM-CSF, and IL-17. Subsequently, the transcriptomic analysis showed that SLS inhibited the IL-17 signaling pathway and the apoptosis signaling pathway of T cells. In addition, SLS downregulated the expression of IL-17A, IL-6, TNF-α, GM-CSF, S100A8, CASP 7, CASP 9, and CASP 10 in anti-CD19 CAR-T cells. SLS regulated the IL-17 signaling pathway and apoptosis signaling pathway in anti-CD19 CAR-T cells. CONCLUSION SLS plays a potential auxiliary role in enhancing the function of anti-CD19 CAR T cells in the treatment of B-cell lymphoma, improving the killing ability of these cells, reducing the potential risk associated with inflammation, and providing synergistic and attenuating effects. The mechanism of SLS is partially mediated by the apoptosis and IL-17 signaling pathways (such as IL-17A, IL-6, TNF-α, GM-CSF, and Granzyme B).
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Affiliation(s)
- Shi Dong
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China; Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 101121, China
| | - Peipei Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China
| | - Liubo Zhang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiaotian Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China
| | - Xiaorui Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China
| | - Jiali Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China
| | - Xinming Cui
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China
| | - Ting Lan
- Department of Lab Medicine, Zhongshan People's Hospital, Zhongshan, 528403, China
| | - Can Gao
- Department of Lab Medicine, Zhongshan People's Hospital, Zhongshan, 528403, China
| | - Yuanyuan Shi
- Shenzhen Research Institute of Chinese Medicine, Shenzhen, 518172, China; Shenzhen Cell Valley Biomedical Co., Ltd, Shenzhen, 518000, China
| | - Weijia Wang
- Department of Lab Medicine, Zhongshan People's Hospital, Zhongshan, 528403, China.
| | - Jianxun Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102401, China; Shenzhen Research Institute of Chinese Medicine, Shenzhen, 518172, China; Shenzhen Cell Valley Biomedical Co., Ltd, Shenzhen, 518000, China.
| | - Miao Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 101121, China.
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Huldani H, Abdul-Jabbar Ali S, Al-Dolaimy F, Hjazi A, Denis Andreevich N, Oudaha KH, Almulla AF, Alsaalamy A, Kareem Oudah S, Mustafa YF. The potential role of interleukins and interferons in ovarian cancer. Cytokine 2023; 171:156379. [PMID: 37757536 DOI: 10.1016/j.cyto.2023.156379] [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: 09/03/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 09/29/2023]
Abstract
Ovarian cancer poses significant challenges and remains a highly lethal disease with limited treatment options. In the context of ovarian cancer, interleukins (ILs) and interferons (IFNs), important cytokines that play crucial roles in regulating the immune system, have emerged as significant factors influencing its development. This article provides a comprehensive review of the involvement of various ILs, including those from the IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family, and IL-17 family, in ovarian cancer. The focus is on their impact on tumor growth, metastasis, and their role in evading immune responses within the tumor microenvironment. Additionally, the article conducts an in-depth examination of the oncogenic or antitumor roles of each IL in the context of ovarian cancer pathogenesis and progression. Besides, we elucidated the enhancements in the treatment of ovarian cancer through the utilization of type-I IFN and type-II IFN. Recent research has shed light on the intricate mechanisms through which specific ILs and IFNs contribute to the advancement of the disease. By incorporating recent findings, this review also seeks to inspire further investigations into unexplored mechanisms, fostering ongoing research to develop more effective therapeutic strategies for ovarian cancer. Moreover, through an in-depth analysis of IL- and IFN-associated clinical trials, we have highlighted their promising potential of in the treatment of ovarian cancer. These clinical trials serve to reinforce the significant outlook for utilizing ILs and IFNs as therapeutic agents in combating this disease.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Faculty of Medicine, Lambung Mangkurat University, Banjarmasin, South Kalimantan, Indonesia
| | | | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Khulood H Oudaha
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Abbas F Almulla
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Shamam Kareem Oudah
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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Chen W, Liu H, Huang X, Qian L, Chen L, Zhou Y, Liu Y, Liu Y, Wang Y, Zhang T, Zhou Y, Fang J, Yang J, Ni F, Guo C, Zhou Y. A single-cell landscape of pre- and post-menopausal high-grade serous ovarian cancer ascites. iScience 2023; 26:107712. [PMID: 37701567 PMCID: PMC10493500 DOI: 10.1016/j.isci.2023.107712] [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: 05/12/2023] [Revised: 07/23/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
High-grade serous ovarian cancer (HGSOC) is a hormone-related cancer with high mortality and poor prognosis. Based on the transcriptome of 57,444 cells in ascites from 10 patients with HGSOC (including 5 pre-menopausal and 5 post-menopausal patients), we identified 14 cell clusters which were further classified into 6 cell types, including T cells, B cells, NK cells, myeloid cells, epithelial cells, and stromal cells. We discovered an increased proportion of epithelial cells and a decreased proportion of T cells in pre-menopausal ascites compared with post-menopausal ascites. GO analysis revealed the pre-menopausal tumor microenvironments (TME) are closely associated with viral infection, while the post-menopausal TME are mostly related to the IL-17 immune pathway. SPP1/CD44-mediated crosstalk between myeloid cells and B cells, NK cells, and stromal cells mainly present in the pre-menopausal group, while SPP1/PTGER4 -mediated crosstalk between myeloid cells and epithelial cells mostly present in the post-menopausal group.
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Affiliation(s)
- Wenying Chen
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Hanyuan Liu
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Xinya Huang
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Lili Qian
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Liang Chen
- Department of Cardiology, The First Affiliated Hospital of USTC, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yonggang Zhou
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yi Liu
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Yujie Liu
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Yingying Wang
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Tianjiao Zhang
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Youyang Zhou
- HanGene Biotech, Xiaoshan Innovation Polis, Hangzhou, Zhejiang 31200, China
| | - Jingwen Fang
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230021, China
- HanGene Biotech, Xiaoshan Innovation Polis, Hangzhou, Zhejiang 31200, China
| | - Jiaxuan Yang
- HanGene Biotech, Xiaoshan Innovation Polis, Hangzhou, Zhejiang 31200, China
| | - Fang Ni
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
- Department of Hematology, The First Affiliated Hospital of USTC, Hefei, Anhui, China
| | - Chuang Guo
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230021, China
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
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Margul D, Yu C, AlHilli MM. Tumor Immune Microenvironment in Gynecologic Cancers. Cancers (Basel) 2023; 15:3849. [PMID: 37568665 PMCID: PMC10417375 DOI: 10.3390/cancers15153849] [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: 06/07/2023] [Revised: 07/23/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer's molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer. Knowledge of the role of the TIME in gynecologic cancers has been rapidly developing with a large body of preclinical studies demonstrating an intricate yet dichotomous role that the immune system plays in either supporting the growth of cancer or opposing it and facilitating effective treatment. Many targets and therapeutics have been identified including cytokines, antibodies, small molecules, vaccines, adoptive cell therapy, and bacterial-based therapies but most efforts in gynecologic cancers to utilize them have not been effective. However, with the development of immune checkpoint inhibitors, we have started to see the rapid and successful employment of therapeutics in cervical and endometrial cancer. There remain many challenges in utilizing the TIME, particularly in ovarian cancer, and further studies are needed to identify and validate efficacious therapeutics.
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Affiliation(s)
| | | | - Mariam M. AlHilli
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cleveland Clinic, Cleveland, OH 44195, USA; (D.M.); (C.Y.)
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11
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Gao Z, Bai Y, Lin A, Jiang A, Zhou C, Cheng Q, Liu Z, Chen X, Zhang J, Luo P. Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment. Mol Cancer 2023; 22:31. [PMID: 36793048 PMCID: PMC9930367 DOI: 10.1186/s12943-023-01722-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/16/2023] [Indexed: 02/17/2023] Open
Abstract
As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.
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Affiliation(s)
- Zhifei Gao
- grid.284723.80000 0000 8877 7471The Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong 510282 People’s Republic of China ,grid.284723.80000 0000 8877 7471The Second Clinical Medical School, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 People’s Republic of China
| | - Yifeng Bai
- grid.54549.390000 0004 0369 4060The Department of Oncology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 611731 China
| | - Anqi Lin
- grid.284723.80000 0000 8877 7471The Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong 510282 People’s Republic of China
| | - Aimin Jiang
- grid.73113.370000 0004 0369 1660The Department of Urology, Changhai hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Chaozheng Zhou
- grid.284723.80000 0000 8877 7471The Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong 510282 People’s Republic of China ,grid.284723.80000 0000 8877 7471The First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Quan Cheng
- grid.216417.70000 0001 0379 7164The Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan China ,grid.216417.70000 0001 0379 7164National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zaoqu Liu
- grid.412633.10000 0004 1799 0733The Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Xin Chen
- The Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Jian Zhang
- The Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, 510282, People's Republic of China.
| | - Peng Luo
- The Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, 510282, People's Republic of China.
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12
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Shi L, Lu J, Zhong D, Song M, Liu J, You W, Li WH, Lin L, Shi D, Chen Y. Clinicopathological and predictive value of MAIT cells in non-small cell lung cancer for immunotherapy. J Immunother Cancer 2023; 11:jitc-2022-005902. [PMID: 36657812 PMCID: PMC9853268 DOI: 10.1136/jitc-2022-005902] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/02/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Immune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment. METHODS To investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing. RESULTS MAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients. CONCLUSIONS MAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy.
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Affiliation(s)
- Lin Shi
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China,Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China
| | - Jinying Lu
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Da Zhong
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China
| | - Meijuan Song
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Liu
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Wenhua You
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Wen-Hui Li
- Department of Hepatobiliary Surgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, The Third People’s Hospital of Yancheng, Yancheng, China
| | - Lin Lin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongyan Shi
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China
| | - Yun Chen
- Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China,Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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13
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PD-L1: expression regulation. BLOOD SCIENCE 2023; 5:77-91. [DOI: 10.1097/bs9.0000000000000149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/29/2022] [Indexed: 02/05/2023] Open
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Lian J, Liang Y, Zhang H, Lan M, Ye Z, Lin B, Qiu X, Zeng J. The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment. Front Immunol 2022; 13:912279. [PMID: 36119047 PMCID: PMC9479087 DOI: 10.3389/fimmu.2022.912279] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.
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Affiliation(s)
- Jiachun Lian
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
| | - Hailiang Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Minsheng Lan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Ziyu Ye
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
| | - Bihua Lin
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Xianxiu Qiu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Jincheng Zeng
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Collaborative Innovation Center for Antitumor Active Substance Research and Development, Zhanjiang, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
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15
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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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16
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Liontos M, Andrikopoulou A, Koutsoukos K, Markellos C, Skafida E, Fiste O, Kaparelou M, Thomakos N, Haidopoulos D, Rodolakis A, Dimopoulos MA, Zagouri F. Neutrophil-to-lymphocyte ratio and chemotherapy response score as prognostic markers in ovarian cancer patients treated with neoadjuvant chemotherapy. J Ovarian Res 2021; 14:148. [PMID: 34724958 PMCID: PMC8561989 DOI: 10.1186/s13048-021-00902-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. RESULTS Median age was 64.57 years (SD: 9.72; range 39.2-87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42-14.67)) and 34.69 months (95% CI: 23.26-46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). CONCLUSION NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS.
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Affiliation(s)
- M Liontos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
| | - A Andrikopoulou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Koutsoukos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - C Markellos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - E Skafida
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - O Fiste
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M Kaparelou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - N Thomakos
- Department of Obstetrics and Gynecology, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - D Haidopoulos
- Department of Obstetrics and Gynecology, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - A Rodolakis
- Department of Obstetrics and Gynecology, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M A Dimopoulos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - F Zagouri
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Zhang D, Zou D, Deng Y, Yang L. Systematic analysis of the relationship between ovarian cancer prognosis and alternative splicing. J Ovarian Res 2021; 14:120. [PMID: 34526089 PMCID: PMC8442315 DOI: 10.1186/s13048-021-00866-1] [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: 05/02/2021] [Accepted: 06/30/2021] [Indexed: 11/10/2022] Open
Abstract
Background Ovarian cancer(OC) is the gynecological tumor with the highest mortality rate, effective biomarkers are of great significance in improving its prognosis. In recent years, there have been many studies on alternative splicing (AS) events, and the role of AS events in tumor has become a focus of attention. Methods Data were downloaded from the TCGA database and Univariate Cox regression analysis was performed to determine AS events associated with OC prognosis.Eight prognostic models of OC were constructed in R package, and the accuracy of the models were evaluated by the time-dependent receiver operating characteristic (ROC) curves.Eight types of survival curves were drawn to evaluate the differences between the high and low risk groups.Independent prognostic factors of OC were analyzed by single factor independent analysis and multi-factor independent prognostic analysis.Again, Univariate Cox regression analysis was used to analyze the relationship between splicing factors(SF) and AS events, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were performed on OS-related SFs to understand the pathways. Results Univariate Cox regression analysis showed that among the 15,278 genes, there were 31,286 overall survival (OS) related AS events, among which 1524 AS events were significantly correlated with OS. The area under the time-dependent receiver operating characteristic curve (AUC) of AT and ME were the largest and the RI was the smallest,which were 0.757 and 0.68 respectively. The constructed models have good value for the prognosis assessment of OC patients. Among the eight survival curves, AP was the most significant difference between the high and low risk groups, with a P value of 1.61e − 1.The results of single factor independent analysis and multi-factor independent prognostic analysis showed that risk score calculated by the model and age could be used as independent risk factors.According to univariate COX regression analysis,109 SFs were correlated with AS events and adjusted in two ways: positive and negative. Conclusions SFs and AS events can directly or indirectly affect the prognosis of OC patients. It is very important to find effective prognostic markers to improve the survival rate of OC. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-021-00866-1.
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Affiliation(s)
- Di Zhang
- Department of Gynaecology, the 2nd Afliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Dan Zou
- Department of Gynaecology, the 2nd Afliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yue Deng
- Department of Gynaecology, the 2nd Afliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Lihua Yang
- Department of Gynaecology, the 2nd Afliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Investigation of IL-17A Serum Levels in Patients with Nonmelanoma Skin Cancer. Dermatol Res Pract 2021; 2021:5540163. [PMID: 34239554 PMCID: PMC8233089 DOI: 10.1155/2021/5540163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/11/2021] [Indexed: 01/13/2023] Open
Abstract
Background Role of interleukin 17A (IL-17A) in carcinogenesis and cancer growth is controversial. Although some researches support its antitumor activity, some others suggest that it promotes the growth and development of different types of cancer including skin cancer by activation of STAT3. Although the function of the cytokines such as IL-17A has been extensively studied in various types of cancer, nonmelanoma skin cancer (NMSC) has not received much attention. Therefore, the present study was aimed to investigate the serum levels of IL-17A in NMSC patients. Methods This cross-sectional study was performed on 60 patients with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as well as 57 age-sex matched healthy individuals as control group. Measurement of IL-17A serum levels in both case and control groups was performed by a commercially reliable sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results In this study, we observed that IL-17A serum levels in NMSC patients were significantly higher than the control group (P < 0.001). Also, both BCC and SCC patients had higher levels of IL-17A in their sera in comparison to the controls (P=0.001 and P < 0.001, respectively). However, there was no significant difference between SCC and BCC patients regarding serum levels of IL-17A. Conclusion According to our results, it can be concluded that IL-17A may play a role in inducing the growth and progression of NMSC and it can be used as a therapeutic target in these patients in future.
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Li H, Liu H, Fu H, Li J, Xu L, Wang G, Wu H. Peritumoral Tertiary Lymphoid Structures Correlate With Protective Immunity and Improved Prognosis in Patients With Hepatocellular Carcinoma. Front Immunol 2021; 12:648812. [PMID: 34122408 PMCID: PMC8187907 DOI: 10.3389/fimmu.2021.648812] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/10/2021] [Indexed: 02/05/2023] Open
Abstract
The existence of intratumoral tertiary lymphoid structure (iTLS) has been reported to correlative with favorable clinical outcomes for patients with hepatocellular carcinoma (HCC). However, little is known about the role of peritumoral TLS (pTLS). This study aimed to investigate the prognostic role of pTLS either alone or jointly with iTLS and the potential association with local immune response in HCC. The formation and cellular composition of TLS was evaluated by hematoxylin & eosin and immunohistochemistry. Evaluation of tumor-infiltrating immune cells and formation of germinal center (GC) inside TLS was performed by immunohistochemistry. The gene expression profiles were analyzed by real-time PCR. In a total of 360 patients from two independent cohorts, the pTLS was identified in most, whereas iTLS could be observed in only approximately 30% of HCC specimens. Patients with high pTLS densities were associated with improved outcomes, those present with characteristic morphology of GC, particularly, showing an even better prognosis. The combination of pTLS and iTLS allowed the identification of patients with best prognosis. Tumors with high pTLS density showed significantly increased expression of Th1-, Th17- and immune suppression-related genes, as well as significantly higher infiltration of CD3+, CD8+ and CD20+ cells and lower infiltration of FOXP3+, CD68+ and PD1+ cells. Conclusively, we provide evidence that pTLS is associated with intratumoral immune infiltration, highlighting the dynamic interplay between pTLS and immune cells recruitment. High pTLS density links to a tumor microenvironment with an active immune reaction and improved patient survival and represents a promising prognostic biomarker for HCC.
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Affiliation(s)
- Hui Li
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Hailing Liu
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyuan Fu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Jiaxin Li
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Xu
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Genshu Wang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hong Wu
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
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20
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Li Y, Li G, Zhang J, Wu X, Chen X. The Dual Roles of Human γδ T Cells: Anti-Tumor or Tumor-Promoting. Front Immunol 2021; 11:619954. [PMID: 33664732 PMCID: PMC7921733 DOI: 10.3389/fimmu.2020.619954] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
γδ T cells are the unique T cell subgroup with their T cell receptors composed of γ chain and δ chain. Unlike αβ T cells, γδ T cells are non-MHC-restricted in recognizing tumor antigens, and therefore defined as innate immune cells. Activated γδ T cells can promote the anti-tumor function of adaptive immune cells. They are considered as a bridge between adaptive immunity and innate immunity. However, several other studies have shown that γδ T cells can also promote tumor progression by inhibiting anti-tumor response. Therefore, γδ T cells may have both anti-tumor and tumor-promoting effects. In order to clarify this contradiction, in this review, we summarized the functions of the main subsets of human γδ T cells in how they exhibit their respective anti-tumor or pro-tumor effects in cancer. Then, we reviewed recent γδ T cell-based anti-tumor immunotherapy. Finally, we summarized the existing problems and prospect of this immunotherapy.
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Affiliation(s)
- Yang Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Gen Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jian Zhang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoli Wu
- School of Life Sciences, Tian Jin University, Tian Jin, China
| | - Xi Chen
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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21
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Liu C, Liu R, Wang B, Lian J, Yao Y, Sun H, Zhang C, Fang L, Guan X, Shi J, Han S, Zhan F, Luo S, Yao Y, Zheng T, Zhang Y. Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer. J Immunother Cancer 2021; 9:jitc-2020-001895. [PMID: 33462141 PMCID: PMC7813395 DOI: 10.1136/jitc-2020-001895] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models. METHODS The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors. RESULTS Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors. CONCLUSIONS IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.
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Affiliation(s)
- Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Ruiqi Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jie Lian
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Haoxiu Sun
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Chunhui Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lin Fang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Guan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiaqi Shi
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shuling Han
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Fei Zhan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shengnan Luo
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China .,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China .,Heilongjiang Cancer Institute, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China .,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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22
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Shuai C, Yang X, Pan H, Han W. Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8 + T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer. Front Oncol 2020; 10:582863. [PMID: 33102239 PMCID: PMC7545792 DOI: 10.3389/fonc.2020.582863] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/25/2020] [Indexed: 12/22/2022] Open
Abstract
Background: The relationship between the interleukin 17 (IL-17) family of cytokines and breast cancer has been widely studied in recent years. Many studies have revealed increased levels of the cytokine IL-17A in estrogen receptor (ER)-negative or triple-negative breast cancer. Upregulation of IL-17A signaling is associated with increased expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer with low ER expression and may elevate the infiltration of CD8+ T cells in tumor tissue. This study aims to determine whether ER downregulates the expression of PD-1/PD-L1, reduces the infiltration of CD8+ T cells, and affects the immune microenvironment by decreasing T-helper 17 (Th17) cell infiltration and inhibiting IL-17 signaling in breast cancer. Methods: Samples in The Cancer Genome Atlas Breast Cancer dataset were grouped by ER status and the PAM50 intrinsic subtype. The expression of IL-17 family cytokines and Th17 cell signature cytokines were compared between groups. IL-17 signaling pathway-related genes that were differentially expressed according to the ER level were identified. The PD-1 and PD-L1 levels were compared between breast cancer samples with different ER statuses and IL-17A/IL-17F expression levels. Correlation analyses of the expression of PD-1/PD-L1 and IL-17 signaling pathway-related genes were performed. The associations of the expression of IL-17 signaling pathway-related genes with the immune microenvironment were investigated. Results: High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (IL25), which acts as a suppressor of IL-17 signaling. The expression levels of Th17 cell signature cytokines were significantly increased in ER-negative breast cancer. The expression levels of genes encoding downstream products of IL-17A/IL-17F signaling were downregulated in breast cancer with high ER expression. Increased expression of PD-1/PD-L1 was associated with ER-negative status, IL-17A-positive status, IL-17F-positive status, and upregulation of IL-17 signaling pathway-related genes in breast cancer. Enhanced IL-17 signal transduction was associated with the elevation of CD8+ T cell infiltration and variation of the immune microenvironment of breast cancer. Conclusion: High estrogen receptor levels decrease PD-1/PD-L1 expression and CD8+ T cell infiltration by suppressing Th17 cell infiltration and IL-17 signal transduction in breast cancer.
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Affiliation(s)
- Chong Shuai
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinmei Yang
- Department of Oncology, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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23
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Ma R, Yuan D, Guo Y, Yan R, Li K. Immune Effects of γδ T Cells in Colorectal Cancer: A Review. Front Immunol 2020; 11:1600. [PMID: 33013819 PMCID: PMC7509400 DOI: 10.3389/fimmu.2020.01600] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022] Open
Abstract
Gamma delta (γδ) T cells can effectively recognize and kill colorectal cancer (CRC) cells, thereby suppressing tumor progression via multiple mechanisms. They also have abilities to exert a protumor effect via secreting interleukin-17 (IL-17). γδ T cells have been selected as potential immunocytes for antitumor treatment because of their significant cytotoxic activity. Immunotherapy is another potential anti-CRC strategy after an operation, chemotherapy, and radiotherapy. γδ T cell-based immunotherapy for CRC shows fewer side effects and better toleration. This review will outline the immune functions and the mechanisms of γδ T cells in the growth and progression of CRC in recent years, and summarize the immunotherapies based on γδ T cells, thus providing a direction for future γδ T cells in CRC research.
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MESH Headings
- Animals
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Colorectal Neoplasms/etiology
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/therapy
- Cytokines/metabolism
- Cytotoxicity, Immunologic
- Disease Susceptibility/immunology
- Humans
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Inflammatory Bowel Diseases/complications
- Inflammatory Bowel Diseases/etiology
- Inflammatory Bowel Diseases/metabolism
- Intraepithelial Lymphocytes/immunology
- Intraepithelial Lymphocytes/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- Treatment Outcome
- Tumor Escape/immunology
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Affiliation(s)
- Rulan Ma
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dawei Yuan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yizhan Guo
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Rong Yan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Kang Li
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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24
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Baci D, Bosi A, Gallazzi M, Rizzi M, Noonan DM, Poggi A, Bruno A, Mortara L. The Ovarian Cancer Tumor Immune Microenvironment (TIME) as Target for Therapy: A Focus on Innate Immunity Cells as Therapeutic Effectors. Int J Mol Sci 2020; 21:3125. [PMID: 32354198 PMCID: PMC7247443 DOI: 10.3390/ijms21093125] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/24/2020] [Accepted: 04/26/2020] [Indexed: 12/27/2022] Open
Abstract
Ovarian cancer (OvCA) accounts for one of the leading causes of death from gynecologic malignancy. Despite progress in therapy improvements in OvCA, most patients develop a recurrence after first-line treatments, dependent on the tumor and non-tumor complexity/heterogeneity of the neoplasm and its surrounding tumor microenvironment (TME). The TME has gained greater attention in the design of specific therapies within the new era of immunotherapy. It is now clear that the immune contexture in OvCA, here referred as tumor immune microenvironment (TIME), acts as a crucial orchestrator of OvCA progression, thus representing a necessary target for combined therapies. Currently, several advancements of antitumor immune responses in OvCA are based on the characterization of tumor-infiltrating lymphocytes, which have been shown to correlate with a significantly improved clinical outcome. Here, we reviewed the literature on selected TIME components of OvCA, such as macrophages, neutrophils, γδ T lymphocytes, and natural killer (NK) cells; these cells can have a role in either supporting or limiting OvCA, depending on the TIME stimuli. We also reviewed and discussed the major (immune)-therapeutic approaches currently employed to target and/or potentiate macrophages, neutrophils, γδ T lymphocytes, and NK cells in the OvCA context.
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Affiliation(s)
- Denisa Baci
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (D.B.); (M.G.); (M.R.); (D.M.N.)
| | - Annalisa Bosi
- Laboratory of Pharmacology, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy;
| | - Matteo Gallazzi
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (D.B.); (M.G.); (M.R.); (D.M.N.)
| | - Manuela Rizzi
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (D.B.); (M.G.); (M.R.); (D.M.N.)
| | - Douglas M. Noonan
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (D.B.); (M.G.); (M.R.); (D.M.N.)
- IRCCS MultiMedica, 20138 Milan, Italy;
| | - Alessandro Poggi
- UOSD Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | | | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (D.B.); (M.G.); (M.R.); (D.M.N.)
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25
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Aotsuka A, Matsumoto Y, Arimoto T, Kawata A, Ogishima J, Taguchi A, Tanikawa M, Sone K, Mori-Uchino M, Tsuruga T, Oda K, Kawana K, Osuga Y, Fujii T. Interleukin-17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma. Cancer Sci 2019; 110:3068-3078. [PMID: 31432577 PMCID: PMC6778630 DOI: 10.1111/cas.14174] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/27/2019] [Accepted: 08/14/2019] [Indexed: 12/28/2022] Open
Abstract
The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin-17 (IL-17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL-17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL-17-producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi-color flow cytometry (Th17: P < 0.0001 and P = 0.0002, respectively; γδT17: P = 0.0020 and P = 0.0084, respectively). IL-17 mRNA level was elevated in PBMC of ovarian cancer patients (P = 0.0029), as measured by RT-PCR. The neutrophil-to-lymphocyte ratio, which is a prognostic biomarker of ovarian cancer, correlated with Th17 occupancy ratio in patients (P = 0.0068). We found that programmed cell death 1 ligand 1 expression and its associated factors (IL-6 and phospho-signal transducer and activator of transcription 3) were induced by IL-17 in an ovarian cancer cell line. These results suggest that increased Th17 counts and IL-17 level, which correlated with high neutrophil-to-lymphocyte ratio and programmed cell death 1 ligand 1 expression, are potential biomarkers for poor prognosis in ovarian cancer and likely indications for application of programmed cell death 1 ligand 1 pathway inhibitors.
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Affiliation(s)
- Aeri Aotsuka
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yoko Matsumoto
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | | | - Akira Kawata
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Juri Ogishima
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Ayumi Taguchi
- Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Michihiro Tanikawa
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Mayuyo Mori-Uchino
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Tetsushi Tsuruga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Katsutoshi Oda
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kei Kawana
- Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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