BCL6 promotes a stem-like CD8 <sup>+</sup> T cell program in cancer via antagonizing BLIMP1
Qinli Sun, Dongli Cai, Dingfeng Liu, Xiaohong Zhao, Ruifeng Li, Wei Xu, Bowen Xie, Mengting Gou, Kun Wei, Yuling Li, Jinling Huang, Xinxin Chi, Peng Wei, Jing Hao, Xinyi Guo, Birui Pan, Yujie Fu, Ling Ni, Chen Dong
Abstract
Overcoming CD8 + T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8 + T cell (T prog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8 + T cell (T term cell) subpopulation with potent cytotoxic functions. T prog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control T prog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific T term cell generation from T prog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of T prog 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 + T prog 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 term cell–associated genes and induced those of T prog cell–related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the T prog 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.