Expression of the transcription factor BATF reduced exhaustion of CAR T cells and sustained tumor inhibition.
Major Finding: Expression of the transcription factor BATF reduced exhaustion of CAR T cells and sustained tumor inhibition.
Concept: Cooperation between BATF and IRF4 enhanced tumor inhibition and promoted memory T-cell formation.
Impact: Countering T-cell exhaustion via induced expression of BATF could improve the efficacy of CAR T-cell therapy.
T-cell exhaustion is a significant issue affecting the efficacy of immunotherapies including immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. CD8+ effector T cells mount sustainable responses to antigen in the presence of costimulatory signals, but without these signals, they lose their ability to effectively kill tumor cells. Using mouse models and CD19-targeting CAR T cells, Seo, González-Avalos, and colleagues performed a screen for transcription factors that could enhance NFAT–AP-1–driven effector functions when expressed in CD8+ CAR T cells to ultimately combat T-cell exhaustion and found that transduction of CAR T cells with basic leucine zipper ATF-like transcription factor (BATF) conferred enhanced antitumor effects in mice engrafted with melanoma and colorectal cancer cell lines. BATF-expressing CAR tumor-infiltrating T lymphocytes (TIL) exhibited an expression profile indicating reduced exhaustion, including the absence of high levels of PD-1 and TOX expression seen in control CAR TILs. BATF induced an effector-like TIL subset with granzyme B and ICOS expression, whereas a separate subset of BATF-expressing CAR TILs retained markers of a progenitor-like state. Mice that had previously been injected with BATF-expressing CAR T cells had persisting cells with memory T-cell characteristics and rejected tumor formation when rechallenged with the same tumor cells. Further analysis revealed cooperation between BATF and another transcription factor, interferon regulatory factor 4 (IRF4), to be vital for the exhaustion resistance phenotype, and CAR T cells expressing a BATF variant with lower affinity for IRF4 did not delay tumor growth or survive in tumors in mice. Expression of BATF is therefore likely to promote increased effector functioning and inhibit processes promoting T-cell exhaustion, though it is likely that other transcription factors have similar roles. Utilization of this knowledge may have potential in limiting T-cell exhaustion following T-cell–dependent therapies to improve responses, particularly in traditionally immunologically “cold” tumor types.
Seo H, González-Avalos E, Zhang W, Ramchandani P, Yang C, Lio CWJ, et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol 2021 Jul 19 [Epub ahead of print].
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