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

Menée à l'aide de lignées cellulaires, d'échantillons de cellules mononucléées du sang périphérique et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel une déplétion du facteur de transcription BATF augmente l'activité antitumorale des lymphocytes CAR-T

Résumé en anglais

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.