期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-020-19833-3
关键词
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资金
- National Cancer Institute [5F31CA213668-02]
- National Institutes of Health [R01CA138738-05, PO1CA059350, PO1CA190174-01, P50CA192937-03]
- Annual Terry Fox Run for Cancer Research (New York, NY)
- Kate's Team
- Cabot Family Charitable Trust
- Leukemia and Lymphoma Society
- William Lawrence and Blanche Hughes Foundation
- Emerald Foundation
- NIH [P30CACA008748]
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. CD40L-expressing chimeric antigen receptor (CAR) T cells show enhanced anti-tumor immunity, but the cellular mechanisms are still unclear. Here we show, by analyzing mice deficient of conventional dendritic cell type 1 (cDC1) that cDC1s are induced by CD40L(+) CAR T cells to prime endogenous CD8 T cells for a stronger anti-tumor immune response.
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