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.
Author Info: (1) Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer
Author Info: (1) Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pathology, University of California San Francisco, San Francisco, CA, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. brentjer@mskcc.org.
