CV1-secreting sCAR-T cells potentiate the abscopal effect of microwave ablation in heterogeneous tumors.

Abstract

Microwave ablation (MWA) triggers a weak systemic immune response that leads to the abscopal regression of distant metastases while killing local tumors, known as the abscopal effect. Combining MWA with chimeric antigen receptor (CAR)-T cells demonstrates promise in enhancing the abscopal effect in antigen-homogeneous tumors. However, the loss of the antigen recognized by CAR or intrinsic antigenic heterogeneity in solid tumors poses a major obstacle. SIRPα variant (CV1)-secreting CAR-T (sCAR-T) cells elicit an abscopal effect on distant tumors with antigen heterogeneity in mice receiving local MWA. Mechanistically, sCAR-T cells can locally eliminate antigen-positive tumors and secrete CV1, whereas the secreted CV1 can activate macrophages that migrate to non-ablated tumor sites in response to post-MWA chemokines, eliciting a macrophage-dependent abscopal effect that enables phagocytosis of antigen-heterogeneous cancer cells. This macrophage-dependent abscopal effect instigated by MWA and sCAR-T cells offers a clinically translatable strategy in metastatic solid tumors with antigen heterogeneity.