Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China.
Sci Immunol. 2023 Oct 27;8(88):eadh1306. doi: 10.1126/sciimmunol.adh1306. Epub 2023 Oct 20.
Overcoming CD8 T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8 T cell (T cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8 T cell (T cell) subpopulation with potent cytotoxic functions. T cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control T cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific T cell generation from T cell downstream of TCF1. We show that deficiency reduced the persistence of T cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOXTCF1 T cells in both LNs and tumors. BCL6 expression in CD8 T cells was up-regulated by TGF-β-SMAD2 signaling but down-regulated by the IL-2-STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of T cell-associated genes and induced those of T cell-related genes, in a manner antagonistic to BLIMP1. deficiency also promoted the T cell program and greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-β-BCL6 and IL-2-BLIMP1 antagonistic pathways in regulation of antitumor CD8 T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.
克服 CD8 T 细胞耗竭在癌症免疫治疗中至关重要。最近，已经定义了一种在肿瘤内介导抗肿瘤反应持续存在的干细胞/祖细胞样 CD8 T 细胞（T 细胞）群体，它可以进一步发展为具有强大细胞毒性功能的终末分化 CD8 T 细胞（T 细胞）亚群。T 细胞是免疫检查点阻断疗法的主要应答者，但转录因子通过外在信号如何控制 T 细胞在肿瘤中的产生和持久性尚不清楚。在这里，我们发现 BCL6 抑制 TCF1 下游的 T 细胞产生肿瘤特异性 T 细胞。我们表明，缺陷减少了 T 细胞的持久性，而不影响其产生，从而消除了长期的肿瘤控制。在引流淋巴结（LN）中的肿瘤特异性 T 细胞中观察到高水平的 BCL6 表达，并与 T 细胞耗竭相关。在 LN 和肿瘤中的 TOXTCF1 T 细胞中均观察到这种情况。TGF-β-SMAD2 信号转导上调 CD8 T 细胞中的 BCL6 表达，而 IL-2-STAT5 途径下调其表达。在机制上，BCL6 通过转录抑制 T 细胞相关基因的表达，并诱导与 T 细胞相关的基因表达，这种方式与 BLIMP1 拮抗。缺陷也促进了 T 细胞程序，并极大地提高了抗 PD-1 治疗的疗效。因此，我们确定了 TGF-β-BCL6 和 IL-2-BLIMP1 拮抗途径在调节抗肿瘤 CD8 T 细胞中的作用，这可能有助于开发持久有效的癌症免疫治疗。
