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Zhu Y, Lu Y, Zhu Y, Ren X, Deng Q, Yang M, Liang X. ST2L promotes VEGFA-mediated angiogenesis in gastric cancer by activating TRAF6/PI3K/Akt/NF-κB pathway via IL-33. Sci Rep 2024; 14:26393. [PMID: 39488565 PMCID: PMC11531471 DOI: 10.1038/s41598-024-76763-6] [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: 06/18/2024] [Accepted: 10/16/2024] [Indexed: 11/04/2024] Open
Abstract
Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.
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Affiliation(s)
- Yanqing Zhu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China
| | - Yuxin Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China
| | - Yifei Zhu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China
| | - Xiaolu Ren
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China
| | - Qinyi Deng
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China
| | - Muqing Yang
- Department of Hepatobilliary Surgical Center, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Putuo District, Shanghai, China.
| | - Xin Liang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, China.
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Geng Q, Lu Y, Li D, Qin L, Qi C, Pu X, Zhuang Y, Zhu Y, Zha Q, Wang G, Jiang H. β-glucan combined with Envafolimab and Endostar as immune rechallenge for metastatic non-small cell lung cancer. BMC Immunol 2024; 25:60. [PMID: 39271997 PMCID: PMC11401293 DOI: 10.1186/s12865-024-00651-x] [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: 07/20/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). β-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received β-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis. RESULTS Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0-6.6] and 9.8 months [95% CI: 7.2-12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response. CONCLUSION β-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.
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Affiliation(s)
- Qian Geng
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Yingying Lu
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Dongqing Li
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Lanqun Qin
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Chunjian Qi
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Xiaolin Pu
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Yi Zhuang
- Department of Oncology, Changzhou Wujin Hospital of TCM, Changzhou, 213003, China
| | - Yajun Zhu
- Department of Oncology, Jintan Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, 213200, China
| | - Quanbin Zha
- Department of Oncology, Jintan Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, 213200, China
| | - Ge Wang
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Hua Jiang
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China.
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Nan Y, Bai Y, Hu X, Zhou K, Wu T, Zhu A, Li M, Dou Z, Cao Z, Zhang X, Xu S, Zhang Y, Lin J, Zeng X, Fan J, Zhang X, Wang X, Ju D. Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy. J Immunother Cancer 2024; 12:e009236. [PMID: 39231544 PMCID: PMC11409265 DOI: 10.1136/jitc-2024-009236] [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] [Accepted: 08/14/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain. METHODS Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB. RESULTS After anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. CONCLUSIONS In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.
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Affiliation(s)
- Yanyang Nan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Yu Bai
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Xiaozhi Hu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Kaicheng Zhou
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Tao Wu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - An Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Mengyang Li
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Zihan Dou
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Zhonglian Cao
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Xumeng Zhang
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA
| | - Shuwen Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Yuanzhen Zhang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Jun Lin
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Jiajun Fan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Xuyao Zhang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Xuebin Wang
- Department of pharmacy, Shanghai Children’s Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dianwen Ju
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
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Arrizabalaga L, Risson A, Ezcurra-Hualde M, Aranda F, Berraondo P. Unveiling the multifaceted antitumor effects of interleukin 33. Front Immunol 2024; 15:1425282. [PMID: 38881897 PMCID: PMC11176530 DOI: 10.3389/fimmu.2024.1425282] [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: 04/29/2024] [Accepted: 05/21/2024] [Indexed: 06/18/2024] Open
Abstract
Interleukin 33 (IL-33), once predominantly recognized for its pro-tumoral activities, has emerged as a multifunctional cytokine with antitumor properties. IL-33 pleiotropic activities include activation of Th1 CD4+ T cells, CD8+ T cells, NK cells, dendritic cells, eosinophils, as well as type 2 innate lymphoid cells. Regarding this immunomodulatory activity, IL-33 demonstrates synergistic interactions with various cancer therapies, including immune checkpoint blockade and chemotherapy. Combinatorial treatments leveraging IL-33 exhibit enhanced antitumor efficacy across different tumor models, promising novel avenues for cancer therapy. Despite its antitumor effects, the complex interplay of IL-33 within the tumor microenvironment underscores the need for further investigation. Understanding the mechanisms underlying IL-33's dual role as both a promoter and inhibitor of tumor progression is essential for refining therapeutic strategies and fully realizing its potential in cancer immunotherapy. This review delves into the intricate landscape of IL-33 effects within the tumor microenvironment, highlighting its pivotal role in orchestrating immune responses against cancer.
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Affiliation(s)
- Leire Arrizabalaga
- Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Aline Risson
- Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Miriam Ezcurra-Hualde
- Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Fernando Aranda
- Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Pedro Berraondo
- Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Park JH, Mortaja M, Son HG, Zhao X, Sloat LM, Azin M, Wang J, Collier MR, Tummala KS, Mandinova A, Bardeesy N, Semenov YR, Mino-Kenudson M, Demehri S. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat Commun 2024; 15:4099. [PMID: 38816352 PMCID: PMC11139893 DOI: 10.1038/s41467-024-48441-8] [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: 04/20/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
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Affiliation(s)
- Jong Ho Park
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea
| | - Mahsa Mortaja
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Heehwa G Son
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Xutu Zhao
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lauren M Sloat
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marjan Azin
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jun Wang
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael R Collier
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Krishna S Tummala
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA
| | - Anna Mandinova
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nabeel Bardeesy
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Yevgeniy R Semenov
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Che K, Luo Y, Song X, Yang Z, Wang H, Shi T, Wang Y, Wang X, Wu H, Yu L, Liu B, Wei J. Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer. EMBO Mol Med 2024; 16:251-266. [PMID: 38238529 PMCID: PMC10897402 DOI: 10.1038/s44321-023-00012-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 09/24/2023] [Accepted: 11/20/2023] [Indexed: 02/17/2024] Open
Abstract
Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.
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Affiliation(s)
- Keying Che
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yuting Luo
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xueru Song
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhe Yang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hanbing Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yue Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xuan Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Hongyan Wu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lixia Yu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
- Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
- Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, China.
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7
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Koroknai V, Szász I, Balázs M. Gene Expression Changes in Cytokine and Chemokine Receptors in Association with Melanoma Liver Metastasis. Int J Mol Sci 2023; 24:ijms24108901. [PMID: 37240247 DOI: 10.3390/ijms24108901] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cytokines and chemokines (chemotactic cytokines) are soluble extracellular proteins that bind to specific receptors and play an integral role in the cell-to-cell signaling network. In addition, they can promote the homing of cancer cells into different organs. We investigated the potential relationship between human hepatic sinusoidal endothelial cells (HHSECs) and several melanoma cell lines for the expression of chemokine and cytokine ligands and receptor expression during the invasion of melanoma cells. In order to identify differences in gene expression related to invasion, we selected invasive and non-invasive subpopulations of cells after co-culturing with HHSECs and identified the gene expression patterns of 88 chemokine/cytokine receptors in all cell lines. Cell lines with stable invasiveness and cell lines with increased invasiveness displayed distinct profiles of receptor genes. Cell lines with increased invasive capacity after culturing with conditioned medium showed a set of receptor genes (CXCR1, IL1RL1, IL1RN, IL3RA, IL8RA, IL11RA, IL15RA, IL17RC, and IL17RD) with significantly different expressions. It is very important to emphasize that we detected significantly higher IL11RA gene expression in primary melanoma tissues with liver metastasis as well, compared to those without metastasis. In addition, we assessed protein expression in endothelial cells before and after co-culturing them with melanoma cell lines by applying chemokine and cytokine proteome arrays. This analysis revealed 15 differentially expressed proteins (including CD31, VCAM-1, ANGPT2, CXCL8, and CCL20) in the hepatic endothelial cells after co-culture with melanoma cells. Our results clearly indicate the interaction between liver endothelial and melanoma cells. Furthermore, we assume that overexpression of the IL11RA gene may play a key role in organ-specific metastasis of primary melanoma cells to the liver.
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Affiliation(s)
- Viktória Koroknai
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - István Szász
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Margit Balázs
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary
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The Cytokine Network in Colorectal Cancer: Implications for New Treatment Strategies. Cells 2022; 12:cells12010138. [PMID: 36611932 PMCID: PMC9818504 DOI: 10.3390/cells12010138] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME). The TME, a heterogeneous population of differentiated and progenitor cells, plays a critical role in regulating tumor development, growth, invasion, metastasis and therapy resistance. In this context, cytokines from cancer cells and cells of the TME influence each other, eliciting an inflammatory milieu that can either enhance or suppress tumor growth and metastasis. Additionally, several lines of evidence exist that the composition of the microbiota regulates inflammatory processes, controlled by cytokine secretion, that play a role in carcinogenesis and tumor progression. In this review, we discuss the cytokine networks between cancer cells and the TME and microbiome in colorectal cancer and the related treatment strategies, with the goal to discuss cytokine-mediated strategies that could overcome the common therapeutic resistance of CRC tumors.
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Yang M, Zeng C, Gong Z, Shao B, Liu G, Bao X, Nie B. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma. Open Life Sci 2022; 17:1657-1668. [PMID: 36567723 PMCID: PMC9755709 DOI: 10.1515/biol-2022-0469] [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: 06/29/2021] [Revised: 06/06/2022] [Accepted: 06/20/2022] [Indexed: 12/23/2022] Open
Abstract
The present study involved building a model of immune-related genes (IRGs) that can predict the survival outcomes of tongue squamous cell carcinoma (TSCC). Using the TCGA database, we collected the gene expression profiles of patients with TSCC and analyzed the differences in IRGs obtained from the ImmPort database. Subsequently, we constructed a predictive model. Transcription factors and differentially expressed IRGs can be used to construct TSCC regulatory network. CIBERSORT tool was used to analyze the relative proportion of 22 tumor-infiltrating immune cells in TSCC samples. Finally, a prognostic model is constructed. We established an IRG model formed by seven genes. The receiver operating characteristic value of the prognostic model based on IRGs is 0.739. After the analysis of the correlation between IRGs and clinical and pathological conditions, we found that Gast was related to grade, IRF9, LTB, and T stage. Among the 22 tumor-infiltrating immune cells, the resting natural killer (NK) cells were found to be related to the 5-year survival rate. This study constructed a prognostic model formed by seven IRGs and discussed the tumor-infiltrating immune cells, which are related to the survival outcome, reflecting the potential regulatory role of TSCC tumor immune microenvironment that could potentially promote individualized treatment.
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Affiliation(s)
- Meng Yang
- Department of Stomatology, Urumqi Stomatological Hospital, No. 196 Zhongshan Road, Tianshan District, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Changyu Zeng
- Center for STD/AIDS Control and Prevention, Xinjiang Uygur Autonomous Regional Center for Disease Control and Prevention, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Zhongcheng Gong
- The Oncological Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Bo Shao
- The Oncological Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Gaocheng Liu
- Department of Stomatology, Urumqi Stomatological Hospital, No. 196 Zhongshan Road, Tianshan District, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xuying Bao
- Department of Stomatology, Urumqi Stomatological Hospital, No. 196 Zhongshan Road, Tianshan District, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Bin Nie
- Department of Stomatology, Urumqi Stomatological Hospital, No. 196 Zhongshan Road, Tianshan District, Xinjiang Uygur Autonomous Region, Urumqi, China
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10
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Lorentz A, Bilotta S, Civelek M. Molecular links between allergy and cancer. Trends Mol Med 2022; 28:1070-1081. [PMID: 35794030 DOI: 10.1016/j.molmed.2022.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/03/2022] [Accepted: 06/03/2022] [Indexed: 01/21/2023]
Abstract
Epidemiologic studies show both positive and negative associations between allergies and cancer. Allergic diseases may protect against tumorigenesis by promoting the immune surveillance, while carcinogenesis may be promoted through inflammatory responses from allergies. Histamine receptor antagonists are the focus of recent cancer studies because of their promising beneficial effect on tumor development. Also, cytokines, particularly IL-4 or IL-33, IgE as well as allergy-related immune cells such as eosinophils can contribute to tumor growth suppression. Depending on cancer types, cancer therapy may be more beneficial when considering combinatorial immunotherapy. In this review, we give an overview on molecular links between allergies and cancer.
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Affiliation(s)
- Axel Lorentz
- Institute of Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany.
| | - Sabrina Bilotta
- Institute of Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany
| | - Mehtap Civelek
- Institute of Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany
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11
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Guo H, Bossila EA, Ma X, Zhao C, Zhao Y. Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions. Cells 2022; 11:cells11203237. [PMID: 36291105 PMCID: PMC9600220 DOI: 10.3390/cells11203237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
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Affiliation(s)
- Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Elhusseny A. Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo 11311, Egypt
| | - Xinran Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Beijing Institute for Stem Cell and Regeneration, Beijing 100101, China
- Correspondence: ; Tel.: +86-10-64807302; Fax: +86-10-64807313
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12
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Jou E, Rodriguez-Rodriguez N, McKenzie ANJ. Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis. Front Immunol 2022; 13:981479. [PMID: 36263033 PMCID: PMC9573978 DOI: 10.3389/fimmu.2022.981479] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/15/2022] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and is largely refractory to current immunotherapeutic interventions. The lack of efficacy of existing cancer immunotherapies in CRC reflects the complex nature of the unique intestinal immune environment, which serves to maintain barrier integrity against pathogens and harmful environmental stimuli while sustaining host-microbe symbiosis during homeostasis. With their expression by barrier epithelial cells, the cytokines interleukin-25 (IL-25) and IL-33 play key roles in intestinal immune responses, and have been associated with inappropriate allergic reactions, autoimmune diseases and cancer pathology. Studies in the past decade have begun to uncover the important roles of IL-25 and IL-33 in shaping the CRC tumour immune microenvironment, where they may promote or inhibit tumorigenesis depending on the specific CRC subtype. Notably, both IL-25 and IL-33 have been shown to act on group 2 innate lymphoid cells (ILC2s), but can also stimulate an array of other innate and adaptive immune cell types. Though sometimes their functions can overlap they can also produce distinct phenotypes dependent on the differential distribution of their receptor expression. Furthermore, both IL-25 and IL-33 modulate pathways previously known to contribute to CRC tumorigenesis, including angiogenesis, tumour stemness, invasion and metastasis. Here, we review our current understanding of IL-25 and IL-33 in CRC tumorigenesis, with specific focus on dissecting their individual function in the context of distinct subtypes of CRC, and the potential prospects for targeting these pathways in CRC immunotherapy.
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Affiliation(s)
- Eric Jou
- MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
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13
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Li Y, Li M, Wang R, Wang B, Athari SS, Wang J. Ganoderma Modulates Allergic Asthma Pathologic Features via Anti-inflammatory Effects. Respir Physiol Neurobiol 2022; 299:103843. [PMID: 35026480 DOI: 10.1016/j.resp.2022.103843] [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: 06/10/2021] [Revised: 10/23/2021] [Accepted: 01/09/2022] [Indexed: 10/19/2022]
Abstract
Ganoderma, a fungal genus, is a traditional medicine with immuno-modulating effects. Asthma is an inflammatory disease of airways, and the main trigger of asthma is allergic inflammation. In this study, the effects of Ganoderma (an anti-inflammatory agent) given via oral administration (G/O) or intraperitoneal injection (G/IP) on asthma was evaluated. Forty BALB/c mice were divided into four groups, including the control, OVA-challenge, OVA-challenge + G/O, and OVA-challenge + G/IP. To determine AHR, the MCh challenge test was done. The levels of IL-1β, -4, -5, -6, -8, -10, -12, -13, -17, -25, -33, -38, Cys-LT, LTB4, and hydroxyproline were measured. Finally, lung histopathology was evaluated to determine eosinophilic inflammation, goblet cell hyperplasia, and mucus hyper-secretion. Treatment with G/O and G/IP could significantly reduce the levels of IL-1β, -5, -6, -8, -17, -25, -33, and -38; the levels of IL-4 and IL-13 had no significant changes, but the levels of IL-10 and IL-12 were enhanced. The mice treated with G/O and G/IP showed decreased levels of Cys-LT, LTB4, peribronchial and perivascular inflammation, but no significant changes were observed in AHR, hydroxyproline level, goblet cell hyperplasia, and mucus hyper-secretion. Ganoderma can be applied as an immunomodulatory and anti-inflammatory agent for managing asthma.
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Affiliation(s)
- Yanfeng Li
- Department of Traditional Chinese Medicine, Xidian Group Hospital, Xi'an city, 710077, People's Republic of China
| | - Miaomiao Li
- Department of Traditional Chinese Medicine, Xidian Group Hospital, Xi'an city, 710077, People's Republic of China
| | - Rui Wang
- Department of Traditional Chinese Medicine, Xidian Group Hospital, Xi'an city, 710077, People's Republic of China
| | - Biyu Wang
- Department of Traditional Chinese Medicine, Xidian Group Hospital, Xi'an city, 710077, People's Republic of China
| | - Seyyed Shamsadin Athari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Jinli Wang
- Department of Traditional Chinese Medicine, Xidian Group Hospital, Xi'an city, 710077, People's Republic of China.
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14
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Huang F, Chen WY, Ma J, He XL, Wang JW. Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential. World J Clin Cases 2022; 10:23-34. [PMID: 35071502 PMCID: PMC8727260 DOI: 10.12998/wjcc.v10.i1.23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/14/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.
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Affiliation(s)
- Fang Huang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Wan-Yuan Chen
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Jie Ma
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Xiang-Lei He
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Jian-Wei Wang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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15
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Mi Z, Zhao L, Sun M, Gao T, Wang Y, Sui B, Li Y. Overexpression of Interleukin-33 in Recombinant Rabies Virus Enhances Innate and Humoral Immune Responses through Activation of Dendritic Cell-Germinal Center Reactions. Vaccines (Basel) 2021; 10:vaccines10010034. [PMID: 35062695 PMCID: PMC8778554 DOI: 10.3390/vaccines10010034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/23/2021] [Accepted: 12/25/2021] [Indexed: 02/08/2023] Open
Abstract
Rabies is a zoonotic infectious disease caused by rabies virus (RABV), and its mortality rate is as high as 100%. Globally, an average of 60,000 people die from rabies each year. The most effective method to prevent and limit rabies is vaccination, but it is currently expensive and inefficient, consisting of a 3-dose series of injections and requiring to be immunized annually. Therefore, it is urgent to develop a single dose of long-acting rabies vaccine. In this study, recombinant rabies virus (rRABV) overexpressing interleukin-33 (IL-33) was constructed and designated as rLBNSE-IL33, and its effect was evaluated in a mouse model. The results showed that rLBNSE-IL33 could enhance the quick production of RABV-induced immune antibodies as early as three days post immunization (dpi) through the activation of dendritic cells (DCs), a component of the innate immune system. Furthermore, rLBNSE-IL33 induced high-level virus-neutralizing antibodies (VNA) production that persisted for 8 weeks by regulating the T cell-dependent germinal center (GC) reaction, thus resulting in better protection against rabies. Our data suggest the IL-33 is a novel adjuvant that could be used to enhance innate and humoral immune responses by activating the DC-GC reaction, and thus, rLBNSE-IL33 could be developed as a safe and effective vaccine for animals.
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Affiliation(s)
- Zhizhong Mi
- College of Basic Medicine, Dali University, Dali 671000, China; (Z.M.); (M.S.); (T.G.); (Y.W.)
| | - Ling Zhao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (B.S.)
| | - Ming Sun
- College of Basic Medicine, Dali University, Dali 671000, China; (Z.M.); (M.S.); (T.G.); (Y.W.)
| | - Ting Gao
- College of Basic Medicine, Dali University, Dali 671000, China; (Z.M.); (M.S.); (T.G.); (Y.W.)
| | - Yong Wang
- College of Basic Medicine, Dali University, Dali 671000, China; (Z.M.); (M.S.); (T.G.); (Y.W.)
| | - Baokun Sui
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (B.S.)
| | - Yingying Li
- College of Basic Medicine, Dali University, Dali 671000, China; (Z.M.); (M.S.); (T.G.); (Y.W.)
- Correspondence: ; Tel.: +86-087-2225-7147
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16
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IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33. Int J Mol Sci 2021; 22:ijms221910602. [PMID: 34638950 PMCID: PMC8508606 DOI: 10.3390/ijms221910602] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 02/05/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner.
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17
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Jiang W, Lian J, Yue Y, Zhang Y. IL-33/ST2 as a potential target for tumor immunotherapy. Eur J Immunol 2021; 51:1943-1955. [PMID: 34131922 DOI: 10.1002/eji.202149175] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/26/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022]
Abstract
IL-33, a member of the IL-1 family, was initially reported to be expressed constitutively in the nucleus of tissue-lining and structural cells. However, upon tissue damage or injury, IL-33 can be released quickly to bind with its cognate receptor ST2 in response to wound healing and inflammation and act as a DAMP. As a key regulator of Th2 responses, IL-33/ST2 signal is primarily associated with immunity and immune-related disorders. In recent years, IL-33/ST2 signaling pathway has been reported to promote the development of cancer and remodel the tumor microenvironment by expanding immune suppressive cells such as myeloid-derived suppressor cells or regulatory T cells. However, its role remains controversial in some tumor settings. IL-33 could also promote effective infiltration of immune cells such as CD8+ T and NK cells, which act as antitumor. These dual effects may limit the clinical application to target this cytokine axis. Therefore, more comprehensive exploration and deeper understanding of IL-33 are required. In this review, we summarized the IL-33/ST2 axis versatile roles in the tumor microenvironment with a focus on the IL-33-target immune cells and downstream signaling pathways. We also discuss how the IL-33/ST2 axis could be used as a potential therapeutic target for cancer immunotherapy.
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Affiliation(s)
- Wenyi Jiang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
| | - Jingyao Lian
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
| | - Ying Yue
- Clinical Laboratory, Henan Medical College Hospital Workers, Zhengzhou, Henan, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China
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18
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The Janus Face of IL-33 Signaling in Tumor Development and Immune Escape. Cancers (Basel) 2021; 13:cancers13133281. [PMID: 34209038 PMCID: PMC8268428 DOI: 10.3390/cancers13133281] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/25/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Interleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target. Abstract Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8+ T cells, regulatory T cells (Treg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy.
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19
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Wang W, Wu J, Ji M, Wu C. Exogenous interleukin-33 promotes hepatocellular carcinoma growth by remodelling the tumour microenvironment. J Transl Med 2020; 18:477. [PMID: 33308251 PMCID: PMC7733302 DOI: 10.1186/s12967-020-02661-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/03/2020] [Indexed: 11/25/2022] Open
Abstract
Background Interleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action. Methods In this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student’s t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software. Results The IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69+ CD8+ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC. Conclusions Taken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.
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Affiliation(s)
- Wenxiu Wang
- Department of Tumour Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Mei Ji
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Changping Wu
- Department of Tumour Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China. .,Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.
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20
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Andreone S, Gambardella AR, Mancini J, Loffredo S, Marcella S, La Sorsa V, Varricchi G, Schiavoni G, Mattei F. Anti-Tumorigenic Activities of IL-33: A Mechanistic Insight. Front Immunol 2020; 11:571593. [PMID: 33329534 PMCID: PMC7734277 DOI: 10.3389/fimmu.2020.571593] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Interleukin-33 (IL-33) is an epithelial-derived cytokine that can be released upon tissue damage, stress, or infection, acting as an alarmin for the immune system. IL-33 has long been studied in the context of Th2-related immunopathologies, such as allergic diseases and parasitic infections. However, its capacity to stimulate also Th1-type of immune responses is now well established. IL-33 binds to its specific receptor ST2 expressed by most immune cell populations, modulating a variety of responses. In cancer immunity, IL-33 can display both pro-tumoral and anti-tumoral functions, depending on the specific microenvironment. Recent findings indicate that IL-33 can effectively stimulate immune effector cells (NK and CD8+ T cells), eosinophils, basophils and type 2 innate lymphoid cells (ILC2) promoting direct and indirect anti-tumoral activities. In this review, we summarize the most recent advances on anti-tumor immune mechanisms operated by IL-33, including the modulation of immune checkpoint molecules, with the aim to understand its potential as a therapeutic target in cancer.
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Affiliation(s)
- Sara Andreone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Jacopo Mancini
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Naples, Italy
| | - Simone Marcella
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Valentina La Sorsa
- Research Coordination and Support Service, CoRI, Istituto Superiore di Sanità, Rome, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Naples, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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