BCL6 promotes a stem-like CD8 + T cell program in cancer via antagonizing BLIMP1

• Published in: Science immunology 2023-10, Vol.8 (88), p.eadh1306-eadh1306
• Main Authors: Sun, Qinli, Cai, Dongli, Liu, Dingfeng, Zhao, Xiaohong, Li, Ruifeng, Xu, Wei, Xie, Bowen, Gou, Mengting, Wei, Kun, Li, Yuling, Huang, Jinling, Chi, Xinxin, Wei, Peng, Hao, Jing, Guo, Xinyi, Pan, Birui, Fu, Yujie, Ni, Ling, Dong, Chen
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adh1306

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. BCL6 and BLIMP1 antagonistically regulate antitumor CD8 + exhausted T cells. Intratumoral exhausted CD8 + stem- or progenitor-like (T prog ) and terminally differentiated (T term ) cells mediate antitumor immunity and response to immunotherapy. Sun et al . investigated how exhausted CD8 + T cells are transcriptionally regulated in murine tumor models, identifying that the transcription factors BCL6 and BLIMP1 reciprocally regulate T prog and T term  cell fates, respectively. BCL6 promoted the long-term persistence of T prog  cells in response to TGF-β–SMAD2 signaling by repressing the T term transcriptional program. Conversely, IL-2–STAT5 signaling repressed BCL6, resulting in BLIMP1 transcription and subsequent T term differentiation. Furthermore, Prdm1 deficiency in tumor-specific CD8 + T cells improved the efficacy of anti–PD-1. Together, these fi