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

Preliminary results and emerging data have shown that lipid droplet high (LD ) immunosuppressive cells accumulate in tumour tissues. By tracking and phenotypic profiling of LD cells, we find that LD CD19 , LD CD11b , and LD 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 CCR7 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 CCR7 immunosuppressive cells from tumour tissues to distal immune organs, indicating an important role for CCR7 in tumour cell-induced immune tolerance. © The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.