Kuhn et al. previously improved antitumor efficacy by engineering CAR T cells to overexpress CD40L, and now found this response dependent on conventional DC1s (cDC1s), but not CD4+ T cells. In A20 lymphoma tumors, treatment with CD40L-overexpressing CD19-CAR T cells increased cDC proliferation and CCR7 expression along with the cDC1/cDC2 ratio, reliant on CD40-CD40L signaling. Tumor-derived CD11b-CD103- cDC precursors proliferated, upregulated IRF8, and could differentiate into cDC1s ex vivo. CD40L-CAR T cell treatment induced long-lived endogenous CD8+ T cell responses capable of controlling CD19-negative A20 tumors.
Contributed by Alex Najibi
ABSTRACT: While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3(-/-) mice lacking the CD103(+) conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b(-)CD103(-) double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8(+) T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses.