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

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors, and one major chal-lenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypo -function 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 eradica-tion 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 anti-tumor activity of CAR-T cells against solid tumors.

Automated summary

Depletion of basic leucine zipper ATF-like transcription factor (BATF) improves the antitumor performance of CAR-T cells against solid tumors, and BATF regulates genes related to exhaustion and development of effector and memory T cells.