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

• Published in: Nature communications Vol. 11; no. 1; pp. 6171 - 10
• Main Authors: Kuhn, Nicholas F, Lopez, Andrea V, Li, Xinghuo, Cai, Winson, Daniyan, Anthony F, Brentjens, Renier J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 02.12.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adaptive Immunity; Animals; Anticancer properties; Antigen Presentation; Antigens; Antigens, CD - genetics; Antigens, CD - immunology; Antitumor activity; Basic-Leucine Zipper Transcription Factors - deficiency; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - immunology; CD103 antigen; CD11b antigen; CD11b Antigen - deficiency; CD11b Antigen - genetics; CD11b Antigen - immunology; CD40 Ligand - genetics; CD40 Ligand - immunology; CD40L protein; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell therapy; Chimeric antigen receptors; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Female; Gene Expression; Immune response; Immune system; Immunity; Immunity, Innate; Immunophenotyping; Immunotherapy; Immunotherapy, Adoptive - methods; Integrin alpha Chains - deficiency; Integrin alpha Chains - genetics; Integrin alpha Chains - immunology; Lymphocytes; Lymphocytes T; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - pathology; Lymphoma, B-Cell - therapy; Memory cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Transplantation; Optimization; Receptors; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Repressor Proteins - deficiency; Repressor Proteins - genetics; Repressor Proteins - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19833-3

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.