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

Nicholas F Kuhn,Xinghuo Li,Winson Cai,Andrea V Lopez,Anthony F Daniyan,Renier J Brentjens

doi:10.1038/s41467-020-19833-3

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.

Highlights

While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization
This study describes the recruitment of tumor-specific endogenous CD8+ T cells after m1928z-CD40L CAR T cell treatment
These findings highlight the induction of a sustained host antitumor response by m1928zCD40L CAR T cells

Summary

Introduction

While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Whereas complete remission after anti-CD19 CAR T cell infusion can be reached in a large fraction of patients, a significant portion of responding patients relapses with CD19-negative disease and others do not respond at all[2,4] This observation warrants improved T cellbased immunotherapies to target and eliminate malignant tumor cells. We have shown that CD40L-overexpressing CAR T cells have an increased antitumor effect, license antigen-presenting cells (APCs) in vivo, activate endogenous T cells, and protect mice from CAR-antigen negative tumor challenge[6]. This strategy is an example of mobilizing immune effectors besides the adoptively transferred CAR.

Methods

Findings

Conclusion