Chimeric Antigen Receptor-Modified Macrophages Trigger Systemic Anti-Tumour Immunity

Preliminary results and emerging data have shown that lipid droplet high (LDhi) immunosuppressive cells accumulate in tumour tissues. By tracking and phenotypic profiling of LDhi 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. (c) The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.