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

Authors :
Do, Mytrang H.
Shi, Wei
Ji, Liangliang
Ladewig, Erik
Zhang, Xian
Srivastava, Raghvendra M.
Capistrano, Kristelle J.
Edwards, Chaucie
Malik, Isha
Nixon, Briana G.
Stamatiades, Efstathios G.
Liu, Ming
Li, Shun
Li, Peng
Chou, Chun
Xu, Ke
Hsu, Ting-Wei
Wang, Xinxin
Chan, Timothy A.
Leslie, Christina S.
Source :
Immunity (10747613). Nov2023, Vol. 56 Issue 11, p2555-2555. 1p.
Publication Year :
2023

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. [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]

Details

Language :
English
ISSN :
10747613
Volume :
56
Issue :
11
Database :
Academic Search Index
Journal :
Immunity (10747613)
Publication Type :
Academic Journal
Accession number :
173518583
Full Text :
https://doi.org/10.1016/j.immuni.2023.10.010