CD103+ cDC1 and endogenous CD8+ T cells are necessary for improved CD40L-overexpressing CAR T cell antitumor function

Nicholas F. Kuhn, Andrea V. Lopez, Xinghuo Li, Winson Cai, Anthony F. Daniyan and Renier J. Brentjens ()
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Nicholas F. Kuhn: Memorial Sloan Kettering Cancer Center
Andrea V. Lopez: Memorial Sloan Kettering Cancer Center
Xinghuo Li: Memorial Sloan Kettering Cancer Center
Winson Cai: Memorial Sloan Kettering Cancer Center
Anthony F. Daniyan: Memorial Sloan Kettering Cancer Center
Renier J. Brentjens: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19833-3

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