PO.IM02.04 · 免疫学
转录因子c-Maf驱动Th17依赖性的CD8⁺ T细胞活化以维持抗肿瘤免疫
Transcription factor c-Maf drives Th17-dependent activation of CD8⁺ T cells to sustain anti-tumor immunity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在肿瘤微环境（TME）中，Th17细胞在肿瘤进展中发挥双重作用。尽管已有报道称IL-17A、IL-17F和IL-21具有抗肿瘤作用，但Th17介导的肿瘤抑制的内在机制仍知之甚少。转录因子c-Maf是CD4⁺ T细胞亚群中细胞因子产生的已知调控因子。为研究其在肿瘤免疫中的作用，我们构建了CD4⁺ T细胞中c-Maf缺陷的小鼠。在皮下肿瘤模型以及AOM/DSS处理诱导的原位结直肠癌模型中，这些小鼠形成的肿瘤显著大于同窝对照组，表明CD4⁺ T细胞中c-Maf的表达对抗肿瘤免疫至关重要。对MC38荷瘤小鼠肿瘤浸润淋巴细胞（TILs）的分析显示，Tbet⁺和IFN-gamma⁺ Th1细胞以及RORgammat⁺、IL-17A⁺和IL-21⁺ Th17细胞显著减少。尽管两种基因型的CD8⁺ T细胞表达的c-Maf水平相当，但c-Maf缺陷小鼠表现出CD8⁺ T细胞细胞毒性显著降低，包括CD107a、granzyme B和IFN-gamma的表达降低。这些发现表明，c-Maf缺陷削弱了抗肿瘤的Th1和Th17反应，并损害了TME内CD8⁺ T细胞的功能。为直接评估c-Maf在Th1和Th17细胞中的作用，我们进行了OT-II⁺ Th1或Th17细胞的过继转移。与WT Th17细胞相比，转移c-Maf缺陷的Th17细胞导致肿瘤控制显著受损，而Th1细胞转移则未显示出基因型依赖性差异。这表明c-Maf选择性地增强Th17细胞的抗肿瘤活性。此外，转移WT OT-II⁺ Th17细胞增强了受体小鼠中CD8⁺ T细胞的细胞毒性，提示c-Maf⁺ Th17细胞促进CD8⁺ T细胞活化。与此一致，当转移到缺乏T细胞和B细胞的Rag1⁻/⁻小鼠中时，WT和c-Maf缺陷的Th17细胞均无法控制肿瘤生长，表明Th17细胞的抗肿瘤活性需要CD8⁺ T细胞。从机制上讲，共培养实验显示，阻断IL-17A或IL-21均可消除WT Th17细胞介导的CD8⁺ T细胞细胞毒性增强。这些结果表明，c-Maf通过调控Th17细胞中IL-17A和IL-21的产生来促进抗肿瘤免疫，从而实现强健的CD8⁺ T细胞活化。总之，我们的发现将c-Maf确定为Th17细胞中的关键转录调控因子，它通过一种增强CD8⁺ T细胞细胞毒功能的细胞因子依赖机制来维持抗肿瘤免疫。
查看英文原文 English abstract
Within the tumor microenvironment (TME), Th17 cells exhibit a dual role in tumor progression. Although IL-17A, IL-17F, and IL-21 have been reported to exert anti-tumor effects, the intrinsic mechanisms underlying Th17-mediated tumor suppression remain poorly understood.The transcription factor c-Maf is a known regulator of cytokine production in CD4⁺ T-cell subsets. To investigate its role in tumor immunity, we generated mice with c-Maf-deficient CD4 + T cells (). In both subcutaneous tumor models and an orthotopic colorectal cancer model induced by AOM/DSS treatment, mice developed significantly larger tumors than littermate controls, demonstrating that c-Maf expression in CD4⁺ T cell is critical for anti-tumor immunity. Analysis of tumor-infiltrating lymphocytes (TILs) from MC38 tumor-bearing mice showed a marked reduction in Tbet⁺ and IFN-gamma⁺ Th1 cells, as well as RORgammat⁺, IL-17A⁺, and IL-21⁺ Th17 cells. Although CD8⁺ T cells expressed comparable levels of c-Maf in both genotypes, mice displayed significantly reduced CD8⁺ T-cell cytotoxicity, including lower expression of CD107a, granzyme B, and IFN-gamma. These findings indicate that c-Maf deficiency diminishes anti-tumor Th1 and Th17 responses and impairs CD8⁺ T-cell function within the TME. To directly assess the role of c-Maf in Th1 and Th17 cells, we performed adoptive transfers of OT-II⁺ Th1 or Th17 cells. Transfer of c-Maf-deficient Th17 cells resulted in significantly impaired tumor control compared to WT Th17 cells, whereas Th1 cell transfer showed no genotype-dependent differences. This indicates that c-Maf selectively enhances the anti-tumor activity of Th17 cells. Furthermore, transfer of WT OT-II⁺ Th17 cells increased CD8⁺ T-cell cytotoxicity in recipient mice, suggesting that c-Maf ⁺ Th17 cells promote CD8⁺ T-cell activation. Consistent with this, neither WT nor c-Maf-deficient Th17 cells controll tumor growth when transferred into Rag1⁻/⁻ mice lacking T and B cells, demonstrating that the anti-tumor activity of Th17 cells requires CD8⁺ T cells. Mechanistically, co-culture experiments revealed that the CD8⁺ T-cell cytotoxic enhancement mediated by WT Th17 cells was abolished upon blockade of either IL-17A or IL-21. These results indicate that c-Maf promotes anti-tumor immunity by regulating IL-17A and IL-21 production in Th17 cells, thereby enabling robust CD8⁺ T-cell activation. In summary, our findings identify c-Maf as a critical transcriptional regulator in Th17 cells that sustains anti-tumor immunity through a cytokine-dependent mechanism that augments CD8⁺ T-cell cytotoxic function.
利益披露 Disclosure
C. Wu, None..
S. Miaw, None.