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.
Keyphrases
- single cell
- cell therapy
- poor prognosis
- induced apoptosis
- gene expression
- lymph node
- transcription factor
- bone marrow
- squamous cell carcinoma
- cell proliferation
- young adults
- mesenchymal stem cells
- quality improvement
- cell cycle arrest
- endoplasmic reticulum stress
- binding protein
- gestational age
- sentinel lymph node
- genome wide
- locally advanced
- replacement therapy
- stress induced