The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
Cell Commun Signal. 2024 Aug 21;22(1):408. doi: 10.1186/s12964-024-01771-y.
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.
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.
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.
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.
越来越多的证据表明，肠道真菌失调在结直肠癌（CRC）的发生和发展中起着关键作用。据报道，肠道真菌通过调节肿瘤免疫来加剧 CRC 的严重程度。我们之前的研究表明，机会性致病真菌病原体热带假丝酵母（Candida tropicalis，C. tropicalis）通过增强 MDSC 的免疫抑制功能并激活 MDSC 的 NLRP3 炎性小体来促进 CRC 的进展。然而，NLRP3 炎性小体激活产生的白细胞介素 1β（IL-1β）与 C. tropicalis 增强的 MDSC 免疫抑制功能之间的关系尚不清楚。
使用 TCGA 数据库分析人 CRC 中 IL-1β与 MDSC 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 MDSC 培养上清进行蛋白质组学分析。进行补充和阻断 IL-1β以及抑制 NLRP3 炎性小体激活的实验。使用 MC38 结肠癌细胞系建立小鼠结肠癌异种移植模型。
CRC 临床样本分析表明，IL-1β的高表达与肿瘤浸润性 MDSC 的免疫抑制功能密切相关。体外实验结果表明，IL-1β是 C. tropicalis 刺激的 MDSC 分泌的最主要细胞因子。体外补充 IL-1β进一步增强了 C. tropicalis 刺激的 MDSC 的免疫抑制功能，NLRP3-IL-1β 轴介导了 C. tropicalis 增强的 MDSC 的免疫抑制功能。最后，阻断 MDSC 分泌的 IL-1β增强了抗肿瘤免疫，减轻了 C. tropicalis 相关的结肠癌。
C. tropicalis 通过 NLRP3 炎性小体促进 MDSC 过度分泌 IL-1β。IL-1β 进一步增强 MDSC 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 MDSC 分泌的 IL-1β可能是治疗 CRC 的一种潜在免疫治疗策略。
