101. Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment.
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Xinming Su, Yalin Xu, Fox, Gregory C., Jingyu Xiang, Kwakwa, Kristin A., Davis, Jennifer L., Belle, Jad I., Wen-Chih Lee, Wong, Wing H., Fontana, Francesca, Hernandez-Aya, Leonel F., Takayuki Kobayashi, Tomasson, Helen M., Junyi Su, Bakewell, Suzanne J., Stewart, Sheila A., Egbulefu, Christopher, Karmakar, Partha, Meyer, Melisa A., and Veis, Deborah J.
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MYELOID cells , *GRANULOCYTE-macrophage colony-stimulating factor , *ARGINASE , *IMMUNE checkpoint proteins , *IMMUNOSUPPRESSION , *ARGININE - Abstract
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 GM-CSF 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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