Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth
Tumor-associated macrophages (TAMs), which commonly express FOLR2 or TREM2, are enriched in solid tumors and keep the tumor microenvironment (TME) immunosuppressed. Here, we introduce IL-12-expressing CAR-T cells targeting FOLR2 or TREM2 to deplete pro-tumor TAMs and reprogram the TME. Treatment with IL-12-armored anti-TAM CAR-T leads to significantly improved survival in metastatic ovarian and lung cancer models. The CAR-T mediates benefit at low cell dose and without lymphodepletion, and remains largely restricted to tumors with no overt toxicity. Spatial transcriptomics reveals that IL-12 anti-TAM CAR-T mediates sustained remodeling of the TME, even after CAR-T contraction, with the expansion of CXCL9+ immunostimulatory macrophages and endogenous tumor-specific cytotoxic T cells. Tumor clearance depends, in part, on FAS expression on cancer cells, revealing an IL-12-FAS axis for IL-12-armored CAR-T activity. These findings position IL-12-producing, myeloid-directed CAR-T as a broad strategy to remodel the TME and drive anti-tumor immunity for solid cancers.
Journal
Cancer CellAuthors
Funding
Investigating Macrophage Molecular and Functional Diversity in Tumor ImmunityDeciphering the molecular control of intratumoral dendritic cellsSpatial functional genomics to identify regulators of the tumor microenvironment and cancer immunityInvestigating disseminated cancer cell clonal cooperation and immune control in dormancy and metastasis