Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells

Cancer Cell. 2022 Nov 14;40(11):1407-1422.e7. doi: 10.1016/j.ccell.2022.09.013. Epub 2022 Oct 13.


Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors, and one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model and found that depletion of basic leucine zipper ATF-like transcription factor (BATF) improved the antitumor performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, loss of BATF endows T cells with improved resistance to exhaustion and superior tumor eradication efficacy. Mechanistically, we found that BATF binds to and up-regulates a subset of exhaustion-related genes in human CAR-T cells. BATF regulates the expression of genes involved in development of effector and memory T cells, and knocking out BATF shifts the population toward a more central memory subset. We demonstrate that BATF is a key factor limiting CAR-T cell function and that its depletion enhances the antitumor activity of CAR-T cells against solid tumors.

Keywords: BATF; CAR-T cell hypofunction model; T cell exhaustion; gene editing; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors* / genetics
  • Basic-Leucine Zipper Transcription Factors* / metabolism
  • Gene Expression Regulation
  • Humans
  • Immunotherapy, Adoptive
  • Mice
  • Neoplasms* / genetics
  • Neoplasms* / therapy
  • Transcription Factors / genetics


  • Basic-Leucine Zipper Transcription Factors
  • Transcription Factors
  • BATF protein, human
  • Batf protein, mouse