Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI145296
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Funding
- National Cancer Institute (NCI), NIH [P01 CA100730]
- NCI [R01 CA216840, R01CA177670]
- US Department of Defense (DoD) [BCRP W81XWH-16-1-0286]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH [R21 AR073507]
- NIAMS [R01 AR070030]
- DDRCC Morphology core [P30 DK52574]
- Barnes-Jewish Foundation
- Washington University MSTP grant [GM07200]
- Hope Center Alafi Neuroimaging Lab (NIH) [S10 RR027552]
- St. Louis Men's Group Against Cancer
- Pat Burkhart Breast Cancer Fund
- Molecular Imaging Center at Washington University (NIH) [NCI P50-CA09056]
- Musculoskeletal Research Center for histology [NIH P30-AR057235]
- NIH [U54CA199092]
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Tumor-infiltrating myeloid cells, induced by breast tumor cell-derived GM-CSF, contribute to an immunosuppressive microenvironment in breast cancer through the regulation of myeloid cell ARG1 expression. Targeting GM-CSF could enhance breast cancer immunotherapy by reversing immune suppression.
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GMCSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.
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