Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis.

Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy. [Display omitted] • MMTV-PyMT mammary tumor parenchyma-located TAMs exhibit low mTORC1 activity • Depletion of TSC1 in TAMs activates mTORC1 and suppresses tumor growth • TSC1-deficient TAMs relocate to a perivascular niche and inhibit angiogenesis • TSC1-deficient TAMs outcompete PROCR-expressing endothelial progenitor cells Tumor neoangiogenesis promotes carcinoma development. Do et al. find that in breast cancer, deletion of the mTORC1 inhibitor TSC1 relocates tumor-associated macrophages (TAMs) to perivascular regions within tumors. There, TAMs outcompete PROCR-expressing endothelial progenitor cells, thereby inhibiting tumor angiogenesis and causing starvation-triggered cancer cell death. [ABSTRACT FROM AUTHOR]