IL-1β mediates Candida tropicalis-induced immunosuppressive function of MDSCs to foster colorectal cancer.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-08-21 DOI:10.1186/s12964-024-01771-y

Zhiyong Zhang, Ying Chen, Xinyi Pan, Pengfei Li, Zhengqian Ren, Xiuzhu Wang, Yuxi Chen, Sunan Shen, Tingting Wang, Aihua Lin

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Abstract

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.

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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。

背景：越来越多的证据表明，肠道真菌菌群失调在结直肠癌（CRC）的发生和发展中起着至关重要的作用。有报道称，肠道真菌通过调节肿瘤免疫加剧了 CRC 的严重程度。我们之前的研究表明，机会致病性真菌病原体热带念珠菌（C. tropicalis）通过增强 MDSCs 的免疫抑制功能和激活 MDSCs 的 NLRP3 炎性体促进 CRC 的进展。然而，NLRP3炎性体激活产生的IL-1β与C. tropicalis增强的MDSCs免疫抑制功能在CRC中的关系仍不清楚：方法：利用TCGA数据库分析人CRC中IL-1β与MDSCs免疫抑制功能相关基因之间的关系。通过免疫荧光染色检测人 CRC 组织中 IL-1β 的表达。对C. tropicalis刺激的MDSCs培养上清进行了蛋白质组学分析。进行了补充和阻断IL-1β以及抑制NLRP3炎性体激活的实验。利用 MC38 结肠癌细胞系建立了小鼠结肠癌异种移植模型：结果：对 CRC 临床样本的分析表明，IL-1β 的高表达与肿瘤浸润 MDSCs 的免疫抑制功能密切相关。体外实验结果显示，IL-1β是MDSCs受C.tropicalis刺激后分泌最多的细胞因子。体外补充IL-1β可进一步增强热带蓟马刺激的MDSCs的免疫抑制功能，NLRP3-IL-1β轴介导热带蓟马增强的MDSCs的免疫抑制功能。最后，阻断MDSCs分泌的IL-1β可增强抗肿瘤免疫力，减轻热带卷尾丝虫相关结肠癌：结论：C. tropicalis通过NLRP3炎性体促进MDSCs过量分泌IL-1β。IL-1β可进一步增强MDSCs的免疫抑制功能，抑制抗肿瘤免疫，从而促进CRC的进展。因此，靶向 MDSCs 分泌的 IL-1β 可能是治疗 CRC 的一种潜在免疫治疗策略。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

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.