Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4. CAR-T-produced IFNy, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.

Automated summary

This study reports a strategy for targeting tumor-associated macrophages (TAMs) using chimeric antigen receptor (CAR) T cells, leading to the depletion of TAMs and enhancing antitumor immunity in mouse models of solid tumors. The CAR T cells effectively killed macrophages without toxicity and promoted the expansion of endogenous CD8 T cells specific for tumor-associated antigens. These findings provide proof of principle for the potential of CAR T-cell therapy in targeting TAMs for cancer treatment.