RESUMEN
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-1ß 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-1ß and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1ß 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-1ß 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-1ß was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1ß was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1ß further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1ß axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1ß secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer. CONCLUSIONS: C. tropicalis promotes excessive secretion of IL-1ß from MDSCs via the NLRP3 inflammasome. IL-1ß further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1ß secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.
Asunto(s)
Candida tropicalis , Neoplasias Colorrectales , Interleucina-1beta , Células Supresoras de Origen Mieloide , Proteína con Dominio Pirina 3 de la Familia NLR , Interleucina-1beta/metabolismo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Animales , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Humanos , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Línea Celular Tumoral , Inflamasomas/metabolismo , Masculino , Ratones Endogámicos C57BL , FemeninoRESUMEN
@#[摘 要] 嵌合抗原受体基因修饰T（CAR-T）细胞免疫治疗被认为是最有前景的肿瘤治疗方法之一，效应CAR-T细胞的数量是决定CAR-T细胞疗法治疗效果的关键因素。CAR-T细胞的体外扩增耗时耗力，回输体内后，CAR-T细胞大量耗竭且难以浸润实体瘤，导致能有效抑制实体瘤的CAR-T细胞数量大幅下降。目前，CAR-T细胞的扩增方法在提高扩增特异性和治疗安全性等方面均存在问题，为CAR-T细胞疗法的临床转化造成困难。近年来，新型免疫激动剂及其下游信号的发现为CAR-T细胞扩增方案提供了更多选择，免疫激动剂给药方式的更新迭代进一步提高了其在体内扩增CAR-T细胞的安全性。本文分析了目前扩增CAR-T细胞面临的挑战，系统阐述了近年来在体内外扩增CAR-T细胞的新策略，为CAR-T细胞疗法的疗效和产能优化提供了新思路。