Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway
Abstract Background Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. Methods Flow cytometry ana...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2019-02-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0530-3 |
| _version_ | 1829519485973823488 |
|---|---|
| author | Yipin Lv Yongliang Zhao Xianhua Wang Na Chen Fangyuan Mao Yongsheng Teng Tingting Wang Liusheng Peng Jinyu Zhang Ping Cheng Yugang Liu Hui Kong Weisan Chen Chuanjie Hao Bin Han Qiang Ma Quanming Zou Jun Chen Yuan Zhuang |
| author_facet | Yipin Lv Yongliang Zhao Xianhua Wang Na Chen Fangyuan Mao Yongsheng Teng Tingting Wang Liusheng Peng Jinyu Zhang Ping Cheng Yugang Liu Hui Kong Weisan Chen Chuanjie Hao Bin Han Qiang Ma Quanming Zou Jun Chen Yuan Zhuang |
| author_sort | Yipin Lv |
| collection | DOAJ |
| description | Abstract Background Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. Methods Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. Results Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. Conclusion Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu. |
| first_indexed | 2024-12-16T14:40:03Z |
| format | Article |
| id | doaj.art-c04fbb6c88084f3497ab89776eb48f24 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-16T14:40:03Z |
| publishDate | 2019-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-c04fbb6c88084f3497ab89776eb48f242022-12-21T22:27:59ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-02-017111510.1186/s40425-019-0530-3Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathwayYipin Lv0Yongliang Zhao1Xianhua Wang2Na Chen3Fangyuan Mao4Yongsheng Teng5Tingting Wang6Liusheng Peng7Jinyu Zhang8Ping Cheng9Yugang Liu10Hui Kong11Weisan Chen12Chuanjie Hao13Bin Han14Qiang Ma15Quanming Zou16Jun Chen17Yuan Zhuang18National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityDepartment of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical UniversityDepartment of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityLa Trobe Institute of Molecular Science, School of Molecular Science, La Trobe UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityAffiliated Hospital of North Sichuan Medical CollegeAffiliated Hospital of North Sichuan Medical CollegeNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityDepartment of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical UniversityNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical UniversityAbstract Background Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. Methods Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. Results Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. Conclusion Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.http://link.springer.com/article/10.1186/s40425-019-0530-3Gastric cancerTumor microenvironmentMast cellsTNF-αPD-L1Immunotherapy |
| spellingShingle | Yipin Lv Yongliang Zhao Xianhua Wang Na Chen Fangyuan Mao Yongsheng Teng Tingting Wang Liusheng Peng Jinyu Zhang Ping Cheng Yugang Liu Hui Kong Weisan Chen Chuanjie Hao Bin Han Qiang Ma Quanming Zou Jun Chen Yuan Zhuang Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway Journal for ImmunoTherapy of Cancer Gastric cancer Tumor microenvironment Mast cells TNF-α PD-L1 Immunotherapy |
| title | Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway |
| title_full | Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway |
| title_fullStr | Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway |
| title_full_unstemmed | Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway |
| title_short | Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway |
| title_sort | increased intratumoral mast cells foster immune suppression and gastric cancer progression through tnf α pd l1 pathway |
| topic | Gastric cancer Tumor microenvironment Mast cells TNF-α PD-L1 Immunotherapy |
| url | http://link.springer.com/article/10.1186/s40425-019-0530-3 |
| work_keys_str_mv | AT yipinlv increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT yongliangzhao increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT xianhuawang increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT nachen increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT fangyuanmao increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT yongshengteng increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT tingtingwang increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT liushengpeng increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT jinyuzhang increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT pingcheng increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT yugangliu increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT huikong increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT weisanchen increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT chuanjiehao increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT binhan increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT qiangma increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT quanmingzou increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT junchen increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway AT yuanzhuang increasedintratumoralmastcellsfosterimmunesuppressionandgastriccancerprogressionthroughtnfapdl1pathway |