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CAR T cells get a STAT tune-up
Adoptive cell therapies using chimeric antigen receptor (CAR) T cells display potent antitumor immunity, but T cell exhaustion can compromise their efficacy. Building on a previous observation that interleukin-7 treatment induced polyfunctional CD4+ T cells producing multiple cytokines, Ding et al. expressed a constitutively active STAT5 variant (CASTAT5) in mouse CD4+ T cells specific for a tumor antigen. CASTAT5-expressing T cells underwent epigenetic remodeling, developed polyfunctionality, and promoted CD8+ T cell–dependent elimination of tumors. In a mouse model of CAR T cells targeting the B cell antigen CD19, CASTAT5 expression in both CD4+ and CD8+ T cells resulted in improved tumor elimination. These findings introduce a new T cell engineering approach for CAR T cells that could yield improved resistance to exhaustion and more robust antitumor activity.
Abstract
The presence of polyfunctional CD4+ T cells is often associated with favorable antitumor immunity. We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4+ T cells drives the development of polyfunctional T cells. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) enabled tumor-specific CD4+ T cells to undergo robust expansion, infiltrate tumors vigorously, and elicit antitumor CD8+ T cell responses in a CD4+ T cell adoptive transfer model system. Integrated epigenomic and transcriptomic analysis revealed that CASTAT5 induced genome-wide chromatin remodeling in CD4+ T cells and established a distinct epigenetic and transcriptional landscape. Single-cell RNA sequencing analysis further identified a subset of CASTAT5-transduced CD4+ T cells with a molecular signature indicative of progenitor polyfunctional T cells. The therapeutic significance of CASTAT5 came from our finding that adoptive transfer of T cells engineered to coexpress CD19-targeting chimeric antigen receptor (CAR) and CASTAT5 gave rise to polyfunctional CD4+ CAR T cells in a mouse B cell lymphoma model. The optimal therapeutic outcome was obtained when both CD4+ and CD8+ CAR T cells were transduced with CASTAT5, indicating that CASTAT5 facilitates productive CD4 help to CD8+ T cells. Furthermore, we provide evidence that CASTAT5 is functional in primary human CD4+ T cells, underscoring its potential clinical relevance. Our results implicate STAT5 as a valid candidate for T cell engineering to generate polyfunctional, exhaustion-resistant, and tumor-tropic antitumor CD4+ T cells to potentiate adoptive T cell therapy for cancer.
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