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

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.