克服 CD8 T 细胞耗竭对于癌症免疫治疗至关重要。最近，定义了介导持续抗肿瘤反应的肿瘤内干/祖细胞样CD8 T细胞（Tprog细胞）群，其可以进一步发育成具有有效细胞毒功能的终末分化CD8 T细胞（Tterm细胞）亚群。 Tprog 细胞是免疫检查点阻断疗法的主要反应者，但通过转录因子的外在信号如何控制 Tprog 细胞的生成和在肿瘤中的持续存在尚不清楚。在这里，我们发现 BCL6 抑制 TCF1 下游 Tprog 细胞产生肿瘤特异性 Tterm 细胞。我们发现，Bcl6 缺陷会降低 Tprog 细胞的持久性，但不会影响其生成，从而消除了对肿瘤的长期控制。在引流淋巴结 (LN) 的肿瘤特异性 T 细胞中观察到高水平的 BCL6 表达，并且与 T 细胞耗竭相关。在 LN 和肿瘤中的 TOX TCF1 Tprog 细胞中都观察到了这一点。 CD8 T 细胞中的 BCL6 表达通过 TGF-β-SMAD2 信号传导上调，但通过 IL-2-STAT5 通路下调。从机制上讲，BCL6 以与 BLIMP1 拮抗的方式转录抑制 Tterm 细胞相关基因的表达并诱导 Tprog 细胞相关基因的表达。 Prdm1缺陷还促进了Tprog细胞程序，并大大提高了抗PD-1治疗的疗效。因此，我们确定了 TGF-β-BCL6 和 IL-2-BLIMP1 拮抗途径在抗肿瘤 CD8 T 细胞的调节中的作用，这可能有利于开发持久有效的癌症免疫疗法。

Overcoming CD8+ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8+ T cell (Tprog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8+ T cell (Tterm cell) subpopulation with potent cytotoxic functions. Tprog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control Tprog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific Tterm cell generation from Tprog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of Tprog 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 TOX+TCF1+ Tprog 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 Tterm cell-associated genes and induced those of Tprog cell-related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the Tprog 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.