Unknown

Dataset Information

0

GM-CSF derived from the inflammatory microenvironment potentially enhanced PD-L1 expression on tumor-associated macrophages in human breast cancer


ABSTRACT: Ever since immune checkpoint inhibitors have been approved for anti-cancer therapy in several cancers, including triple-negative breast cancer, the significance of programmed death-1 ligand 1 (PD-L1) expression in the tumor immune microenvironment has been a topic of interest. In the present study, we investigated the detailed mechanisms of PD-L1 overexpression on tumor-associated macrophages (TAMs) in breast cancer. In in vitro culture studies using human monocyte-derived macrophages, lymphocytes, and breast cancer cell lines, PD-L1 overexpression on macrophages was induced by the conditioned medium (CM) of activated lymphocytes, but not that of cancer cells. Granulocyte–macrophage colony-stimulating factor (GM-CSF) derived from activated lymphocytes was found to be involved in PD-L1 overexpression, in addition to interferon (IFN)-γ, via STAT3 pathway activation. Macrophages suppressed lymphocyte activation, and this inhibition was impaired by PD-1 blocking. The CM of activated lymphocytes also induced the overexpression of PD-L2, but GM-CSF did not affect PD-L2 expression. In the murine E0771 breast cancer model, anti-GM-CSF therapy did not affect PD-L1 expression on TAMs, and the mechanisms of PD-L1 expression on TAMs might differ between humans and mice. However, not only PD-L1, but also PD-L2 was overexpressed on TAMs in the E0771 tumor model, and their expression levels were significantly lower in the tumors in nude mice than in wild-type mice. Anti-PD-L1 antibody and anti-PD-L2 antibody synergistically inhibited E0771 tumor development. In conclusion, PD-L1 and PD-L2 were overexpressed on TAMs, and they potentially contributed to immunosuppression. The GM-CSF-STAT3 pathway is thought to represent a new mechanism of PD-L1 overexpression on TAMs in human breast cancer microenvironment.

SUBMITTER: Yonemitsu K 

PROVIDER: S-EPMC9283541 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC9794780 | biostudies-literature
| S-EPMC6737278 | biostudies-literature
2012-04-12 | E-GEOD-27792 | biostudies-arrayexpress
| S-EPMC8164269 | biostudies-literature
| S-EPMC3679097 | biostudies-literature
2012-04-13 | GSE27792 | GEO
| S-EPMC7201918 | biostudies-literature
| S-EPMC8516467 | biostudies-literature
| S-EPMC5877755 | biostudies-literature
| S-EPMC10399721 | biostudies-literature