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

Sci Immunol. 2023 Oct 27;8(88):eadh1306. doi: 10.1126/sciimmunol.adh1306. Epub 2023 Oct 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes*
  • Humans
  • Interleukin-2
  • Neoplasms*
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta

Substances

  • Interleukin-2
  • Transcription Factors
  • Transforming Growth Factor beta
  • BCL6 protein, human
  • Proto-Oncogene Proteins c-bcl-6