Chimeric antigen receptor-modified macrophages trigger systemic anti-tumour immunity

Abstract

Preliminary results and emerging data have shown that lipid droplet high (LD^hi ) immunosuppressive cells accumulate in tumour tissues. By tracking and phenotypic profiling of LD^hi cells, we find that LD^hi CD19⁺ , LD^hi CD11b⁺ , and LD^hi Ly6G⁺ immune cell populations appear in the spleen, thymus, and tumour tissues in a syngeneic tumour model. Using a contact-dependent reporter system, we discover a LD^hi CCR7^hi immunosuppressive cell population that migrates from tumour tissues to the spleen and thymus. Hence, we engineered a family of chimeric antigen receptor-modified macrophages (CAR-Ms) that direct macrophages to CCR7-positive cells and show that the cytosolic domain from Mer receptor tyrosine kinase (MerTK) triggers tumour cell cytotoxicity by the CAR-Ms. In vivo, CCR7-targeted CAR-Ms suppressed tumour growth and prolonged survival by preventing metastasis and by inducing systemic anti-tumour immunity through retarding the migration of LD^hi CCR7^hi immunosuppressive cells from tumour tissues to distal immune organs, indicating an important role for CCR7 in tumour cell-induced immune tolerance. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: adoptive cell therapy; breast cancer; macrophage.