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Cui X, Liu W, Jiang H, Zhao Q, Hu Y, Tang X, Liu X, Dai H, Rui H, Liu B. IL-12 family cytokines and autoimmune diseases: A potential therapeutic target? J Transl Autoimmun 2025; 10:100263. [PMID: 39759268 PMCID: PMC11697604 DOI: 10.1016/j.jtauto.2024.100263] [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: 10/20/2024] [Revised: 11/28/2024] [Accepted: 12/01/2024] [Indexed: 01/07/2025] Open
Abstract
In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.
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Affiliation(s)
- Xiaoyu Cui
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Wu Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
| | - Hanxue Jiang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
| | - Qihan Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Yuehong Hu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Xinyue Tang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Xianli Liu
- Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100310, China
| | - Haoran Dai
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100310, China
| | - Hongliang Rui
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Baoli Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
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Alam MS, Gaida MM, Witzel HR, Otsuka S, Abbasi A, Guerin T, Abdelmaksoud A, Wong N, Cam MC, Kozlov S, Ashwell JD. TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function. Cell Rep Med 2024; 5:101696. [PMID: 39178856 PMCID: PMC11528236 DOI: 10.1016/j.xcrm.2024.101696] [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: 03/22/2024] [Revised: 06/28/2024] [Accepted: 07/30/2024] [Indexed: 08/26/2024]
Abstract
Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.
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Affiliation(s)
- Muhammad S Alam
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz, 55131 Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Hagen R Witzel
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Shizuka Otsuka
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aamna Abbasi
- Department of Integrative Immunobiology, Duke University, Durham, NC 27708, USA
| | - Theresa Guerin
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Abdalla Abdelmaksoud
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Nathan Wong
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Margaret C Cam
- Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21707, USA
| | - Jonathan D Ashwell
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Bailey JT, Cangialosi S, Moshkani S, Rexhouse C, Cimino JL, Robek MD. CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice. JHEP Rep 2024; 6:101121. [PMID: 39282227 PMCID: PMC11399595 DOI: 10.1016/j.jhepr.2024.101121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 05/14/2024] [Indexed: 09/18/2024] Open
Abstract
Background & Aims HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication. Methods Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8+ T cells were quantified in the spleen and liver at the experimental endpoint. Results CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8+ T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8+ T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg). Conclusions Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4+ T cell-dependent limitation on CD40-mediated antiviral efficacy. Impact and implications Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8+ T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4+ cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.
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Affiliation(s)
- Jacob T Bailey
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Sophia Cangialosi
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Safiehkhatoon Moshkani
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Catherine Rexhouse
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Jesse L Cimino
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Michael D Robek
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
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Farhangnia P, Khorramdelazad H, Nickho H, Delbandi AA. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol 2024; 17:40. [PMID: 38835055 PMCID: PMC11151541 DOI: 10.1186/s13045-024-01561-6] [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: 04/09/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
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Affiliation(s)
- Pooya Farhangnia
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Nickho
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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5
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [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: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Bailey JT, Moshkani S, Rexhouse C, Cimino JL, Robek MD. CD4 + T cells reverse surface antigen persistence in a mouse model of HBV replication. Microbiol Spectr 2023; 11:e0344723. [PMID: 37948314 PMCID: PMC10715182 DOI: 10.1128/spectrum.03447-23] [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: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 11/12/2023] Open
Abstract
IMPORTANCE Hepatitis B virus (HBV) is a leading causative agent of viral hepatitis. A preventative vaccine has existed for decades, but only limited treatment options are available for people living with chronic HBV. Animal models for studying HBV are constrained due to narrow viral tropism, impeding understanding of the natural immune response to the virus. Here, using a vector to overcome the narrow host range and establish HBV replication in mice, we identified the role of helper T cells in controlling HBV. We show that helper T cells promote the B cell's ability to generate antibodies that remove HBV and its associated surface antigen from the blood and that transfer of purified helper T cells from HBV-immunized mice can reverse the accumulation of virus and antigen, furthering our understanding of the immune response to HBV.
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Affiliation(s)
- Jacob T. Bailey
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Safiehkhatoon Moshkani
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Catherine Rexhouse
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Jesse L. Cimino
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Michael D. Robek
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
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7
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Patterson MT, Burrack AL, Xu Y, Hickok GH, Schmiechen ZC, Becker S, Cruz-Hinojoza E, Schrank PR, Kennedy AE, Firulyova MM, Miller EA, Zaitsev K, Williams JW, Stromnes IM. Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma. Cell Rep 2023; 42:112732. [PMID: 37402168 PMCID: PMC10448358 DOI: 10.1016/j.celrep.2023.112732] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 04/21/2023] [Accepted: 06/16/2023] [Indexed: 07/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCIIhi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCIIhi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.
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Affiliation(s)
- Michael T Patterson
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Adam L Burrack
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Yingzheng Xu
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Grant H Hickok
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Zoe C Schmiechen
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Samuel Becker
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Eduardo Cruz-Hinojoza
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Patricia R Schrank
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Ainsley E Kennedy
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Maria M Firulyova
- Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia; National Medical Research Center, Saint-Petersburg, Russia
| | - Ebony A Miller
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
| | - Konstantin Zaitsev
- Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia
| | - Jesse W Williams
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA.
| | - Ingunn M Stromnes
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Masonic Cancer Center and University of Minnesota Medical School, Minneapolis, MN 55414, USA; Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
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Burrack AL, Spartz EJ, Rollins MR, Miller EA, Firulyova M, Cruz E, Goldberg MF, Wang IX, Nanda H, Shen S, Zaitsev K, Stromnes IM. Cxcr3 constrains pancreatic cancer dissemination through instructing T cell fate. Cancer Immunol Immunother 2023; 72:1461-1478. [PMID: 36472588 PMCID: PMC10198906 DOI: 10.1007/s00262-022-03338-7] [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: 09/06/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal and metastatic malignancy resistant to therapy. Elucidating how pancreatic tumor-specific T cells differentiate and are maintained in vivo could inform novel therapeutic avenues to promote T cell antitumor activity. Here, we show that the spleen is a critical site harboring tumor-specific CD8 T cells that functionally segregate based on differential Cxcr3 and Klrg1 expression. Cxcr3+ Klrg1- T cells express the memory stem cell marker Tcf1, whereas Cxcr3-Klrg1 + T cells express GzmB consistent with terminal differentiation. We identify a Cxcr3+ Klrg1+ intermediate T cell subpopulation in the spleen that is highly enriched for tumor specificity. However, tumor-specific T cells infiltrating primary tumors progressively downregulate both Cxcr3 and Klrg1 while upregulating exhaustion markers PD-1 and Lag-3. We show that antigen-specific T cell infiltration into PDA is Cxcr3 independent. Further, Cxcr3-deficiency results in enhanced antigen-specific T cell IFNγ production in primary tumors, suggesting that Cxcr3 promotes loss of effector function. Ultimately, however, Cxcr3 was critical for mitigating cancer cell dissemination following immunotherapy with CD40 agonist + anti-PD-L1 or T cell receptor engineered T cell therapy targeting mesothelin. In the absence of Cxcr3, splenic Klrg1 + GzmB + antitumor T cells wain while pancreatic cancer disseminates suggesting a role for these cells in eliminating circulating metastatic tumor cells. Intratumoral myeloid cells are poised to produce Cxcl10, whereas splenic DC subsets produce Cxcl9 following immunotherapy supporting differential roles for these chemokines on T cell differentiation. Together, our study supports that Cxcr3 mitigates tumor cell dissemination by impacting peripheral T cell fate rather than intratumoral T cell trafficking.
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Affiliation(s)
- Adam L Burrack
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Ellen J Spartz
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Meagan R Rollins
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Ebony A Miller
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Maria Firulyova
- Computer Technologies Laboratory, ITMO University, Saint Petersburg, Russia
| | - Eduardo Cruz
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Michael F Goldberg
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Iris X Wang
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA
| | - Hezkiel Nanda
- Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, MN, 55414, USA
- Clinical Translational Science Institute, University of Minnesota, Minneapolis, MN, USA
| | - Steven Shen
- Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, MN, 55414, USA
- Clinical Translational Science Institute, University of Minnesota, Minneapolis, MN, USA
| | - Konstantin Zaitsev
- Computer Technologies Laboratory, ITMO University, Saint Petersburg, Russia
| | - Ingunn M Stromnes
- Department of Microbiology and Immunology, University of Minnesota Medical School, 2101 6th St SE, 2-186 WMBB, Minneapolis, MN, 55414, USA.
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, 55415, USA.
- Masonic Cancer Center, Minneapolis, USA.
- Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN, 55414, USA.
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9
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Sherman MH, Beatty GL. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. ANNUAL REVIEW OF PATHOLOGY 2023; 18:123-148. [PMID: 36130070 PMCID: PMC9877114 DOI: 10.1146/annurev-pathmechdis-031621-024600] [Citation(s) in RCA: 178] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.
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Affiliation(s)
- Mara H Sherman
- Department of Cell, Developmental and Cancer Biology; and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA;
| | - Gregory L Beatty
- Abramson Cancer Center; and Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
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10
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Liu Y, Ouyang W, Huang H, Tan Y, Zhang Z, Yu Y, Yao H. Identification of a tumor immune-inflammation signature predicting prognosis and immune status in breast cancer. Front Oncol 2023; 12:960579. [PMID: 36713514 PMCID: PMC9881411 DOI: 10.3389/fonc.2022.960579] [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: 06/03/2022] [Accepted: 11/24/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of research on the tumor immune microenvironment. METHODS In this study, data on breast cancer patients were collected from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Differential gene expression analysis, univariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were performed to select overall survival (OS)-related, tumor tissue highly expressed, and immune- and inflammation-related genes. A tumor immune-inflammation signature (TIIS) consisting of 18 genes was finally screened out in the LASSO Cox regression model. Model performance was assessed by time-dependent receiver operating characteristic (ROC) curves. In addition, the CIBERSORT algorithm and abundant expression of immune checkpoints were utilized to clarify the correlation between the risk signature and immune landscape in breast cancer. Furthermore, the association of IL27 with the immune signature was analyzed in pan-cancer and the effect of IL27 on the migration of breast cancer cells was investigated since the regression coefficient of IL27 was the highest. RESULTS A TIIS based on 18 genes was constructed via LASSO Cox regression analysis. In the TCGA-BRCA training cohort, 10-year AUC reached 0.89, and prediction performance of this signature was also validated in the METABRIC set. The high-risk group was significantly correlated with less infiltration of tumor-killing immune cells and the lower expression level of the immune checkpoint. Furthermore, we recommended some small-molecule drugs as novel targeted drugs for new breast cancer types. Finally, the relationship between IL27, a significant prognostic immune and inflammation cytokine, and immune status was analyzed in pan-cancer. Expression of IL27 was significantly correlated with immune regulatory gene expression and immune cell infiltration in pan-cancer. Furthermore, IL27 treatment improved breast cancer cell migration. CONCLUSION The TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status.
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Affiliation(s)
- Yajing Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenhao Ouyang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong Huang
- School of Medicine, Guilin Medical College, Guilin, China
| | - Yujie Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zebang Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yunfang Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Breast Tumor Center, Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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11
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Gamache A, Conarroe C, Adair S, Bauer T, Padilla F, Bullock TNJ. Interrogating the CD27:CD70 axis in αCD40-dependent control of pancreatic adenocarcinoma. Front Cell Dev Biol 2023; 11:1173686. [PMID: 37123403 PMCID: PMC10130518 DOI: 10.3389/fcell.2023.1173686] [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: 02/24/2023] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Immune checkpoint blockade immunotherapy has radically changed patient outcomes in multiple cancer types. Pancreatic cancer is one of the notable exceptions, being protected from immunotherapy by a variety of mechanisms, including the presence of a dense stroma and immunosuppressive myeloid cells. Previous studies have demonstrated that CD40 stimulation can remodel the tumor microenvironment in a manner that promotes effector immune cell responses and can cooperate with immune checkpoint inhibition for durable tumor control mediated by T cells. Here we confirm the capability of this combination therapy to dramatically, and durably, control pancreatic cancer growth in an orthotopic model and that the immune memory to this cancer is primarily a function of CD4+ T cells. We extend this understanding by demonstrating that recruitment of recently primed T cells from the draining lymph nodes is not necessary for the observed control, suggesting that the pre-existing intra-tumoral cells respond to the combination therapy. Further, we find that the efficacy of CD40 stimulation is not dependent upon CD70, which is commonly induced on dendritic cells in response to CD40 agonism. Finally, we find that directly targeting the receptor for CD70, CD27, in combination with the TLR3 agonist polyIC, provides some protection despite failing to increase the frequency of interferon gamma-secreting T cells.
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Affiliation(s)
- Awndre Gamache
- Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, United States
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
- *Correspondence: Awndre Gamache,
| | - Claire Conarroe
- Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, United States
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Sara Adair
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Todd Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Frederic Padilla
- Focused Ultrasound Foundation, Charlottesville, VA, United States
- Department of Radiology, School of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Timothy N. J. Bullock
- Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, United States
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
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12
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Burrack AL, Schmiechen ZC, Patterson MT, Miller EA, Spartz EJ, Rollins MR, Raynor JF, Mitchell JS, Kaisho T, Fife BT, Stromnes IM. Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer. JCI Insight 2022; 7:e151593. [PMID: 35393950 PMCID: PMC9057584 DOI: 10.1172/jci.insight.151593] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 02/18/2022] [Indexed: 01/12/2023] Open
Abstract
We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). We show that tumor antigenicity sculpts myeloid cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, and overcomes macrophage-mediated suppression. The therapeutic activity of adoptive T cell therapy or programmed cell death ligand 1 blockade required cDC1s, which sustained splenic Klrg1+ cytotoxic antitumor T cells and functional intratumoral T cells. KLRG1 and cDC1 genes correlated in human tumors, and PDA patients with high intratumoral KLRG1 survived longer than patients with low intratumoral KLRG1. The immunotherapy CD40 agonist also required host cDC1s for maximal therapeutic benefit. However, CD40 agonist exhibited partial therapeutic benefit in cDC1-deficient hosts and resulted in priming of tumor-specific yet atypical CD8+ T cells with a regulatory phenotype and that failed to participate in tumor control. Monocyte/macrophage depletion using clodronate liposomes abrogated T cell priming yet enhanced the antitumor activity of CD40 agonist in cDC1-deficient hosts via engagement of innate immunity. In sum, our study supports that cDC1s are essential for sustaining effective antitumor T cells and supports differential roles for cDC1s and monocytes/macrophages in instructing T cell fate and immunotherapy response.
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Affiliation(s)
- Adam L. Burrack
- Department of Microbiology and Immunology
- Center for Immunology
| | | | | | - Ebony A. Miller
- Department of Microbiology and Immunology
- Center for Immunology
| | | | | | | | - Jason S. Mitchell
- Center for Immunology
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Brian T. Fife
- Center for Immunology
- Department of Medicine, and
- Masonic Cancer Center, and
| | - Ingunn M. Stromnes
- Department of Microbiology and Immunology
- Center for Immunology
- Masonic Cancer Center, and
- Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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13
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Dong C, Dang D, Zhao X, Wang Y, Wang Z, Zhang C. Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis. Front Immunol 2021; 12:713001. [PMID: 34733272 PMCID: PMC8558420 DOI: 10.3389/fimmu.2021.713001] [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: 05/21/2021] [Accepted: 09/24/2021] [Indexed: 12/11/2022] Open
Abstract
Background IL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma. Methods RNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors. Results Clinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma. Conclusions IL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.
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Affiliation(s)
- Chunyu Dong
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, China
| | - Dan Dang
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Xuesong Zhao
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuanyuan Wang
- Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Zhijun Wang
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, China
| | - Chuan Zhang
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, China
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14
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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15
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Du W, Pasca di Magliano M, Zhang Y. Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer. Front Oncol 2021; 11:682217. [PMID: 34290984 PMCID: PMC8287251 DOI: 10.3389/fonc.2021.682217] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/21/2021] [Indexed: 12/19/2022] Open
Abstract
The stroma-rich, immunosuppressive microenvironment is a hallmark of pancreatic ductal adenocarcinoma (PDA). Tumor cells and other cellular components of the tumor microenvironment, such as cancer associated fibroblasts, CD4+ T cells and myeloid cells, are linked by a web of interactions. Their crosstalk not only results in immune evasion of PDA, but also contributes to pancreatic cancer cell plasticity, invasiveness, metastasis, chemo-resistance, immunotherapy-resistance and radiotherapy-resistance. In this review, we characterize several prevalent populations of stromal cells in the PDA microenvironment and describe how the crosstalk among them drives and maintains immune suppression. We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.
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Affiliation(s)
- Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
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16
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Schmiechen ZC, Stromnes IM. Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma. Front Immunol 2021; 11:613815. [PMID: 33584701 PMCID: PMC7876239 DOI: 10.3389/fimmu.2020.613815] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/10/2020] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.
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Affiliation(s)
- Zoe C. Schmiechen
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Ingunn M. Stromnes
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, United States
- Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN, United States
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