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

Abstract

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.

• Authors: Mytrang H Do, Wei Shi, Liangliang Ji, Erik Ladewig, Xian Zhang, Raghvendra M Srivastava, Kristelle J Capistrano, Chaucie Edwards, Isha Malik, Briana G Nixon, Efstathios G Stamatiades, Ming Liu, Shun Li, Peng Li, Chun Chou, Ke Xu, Ting-Wei Hsu, Xinxin Wang, Timothy A Chan, Christina S Leslie, Ming O Li
• Journal: Immunity (Immunity) Vol. 56 Issue 11 Pg. 2555-2569.e5 (Nov 14 2023) ISSN: 1097-4180 [Electronic] United States
• PMID: 37967531 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Tumor Suppressor Proteins
• TOR Serine-Threonine Kinases
• Tuberous Sclerosis Complex 1 Protein
• Endothelial Protein C Receptor
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Humans
• Tumor Suppressor Proteins
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis Complex 1 Protein (genetics)
• Tumor-Associated Macrophages (metabolism)
• Endothelial Progenitor Cells (metabolism)
• Endothelial Protein C Receptor
• Mechanistic Target of Rapamycin Complex 1
• Neovascularization, Pathologic
• Mammals