{"title":"IL-1β 介导热带念珠菌诱导的 MDSCs 免疫抑制功能，从而诱发结直肠癌。","authors":"Zhiyong Zhang, Ying Chen, Xinyi Pan, Pengfei Li, Zhengqian Ren, Xiuzhu Wang, Yuxi Chen, Sunan Shen, Tingting Wang, Aihua Lin","doi":"10.1186/s12964-024-01771-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear.</p><p><strong>Methods: </strong>The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line.</p><p><strong>Results: </strong>Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer.</p><p><strong>Conclusions: </strong>C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337875/pdf/","citationCount":"0","resultStr":"{\"title\":\"IL-1β mediates Candida tropicalis-induced immunosuppressive function of MDSCs to foster colorectal cancer.\",\"authors\":\"Zhiyong Zhang, Ying Chen, Xinyi Pan, Pengfei Li, Zhengqian Ren, Xiuzhu Wang, Yuxi Chen, Sunan Shen, Tingting Wang, Aihua Lin\",\"doi\":\"10.1186/s12964-024-01771-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear.</p><p><strong>Methods: </strong>The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line.</p><p><strong>Results: </strong>Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer.</p><p><strong>Conclusions: </strong>C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.</p>\",\"PeriodicalId\":55268,\"journal\":{\"name\":\"Cell Communication and Signaling\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337875/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Communication and Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s12964-024-01771-y\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-024-01771-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
IL-1β mediates Candida tropicalis-induced immunosuppressive function of MDSCs to foster colorectal cancer.
Background: There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear.
Methods: The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line.
Results: Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer.
Conclusions: C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.
期刊介绍：
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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