Unknown

Dataset Information

0

Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment.


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.

SUBMITTER: Su X 

PROVIDER: S-EPMC8516467 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3731930 | biostudies-literature
| S-EPMC3829000 | biostudies-literature
| S-EPMC10830720 | biostudies-literature
| S-EPMC9283541 | biostudies-literature
| S-EPMC3613901 | biostudies-other
| S-EPMC6102347 | biostudies-literature
| S-EPMC6759922 | biostudies-literature
| S-EPMC4046249 | biostudies-literature
| S-EPMC7078258 | biostudies-literature
| S-EPMC4527662 | biostudies-literature