@article {3197317,
	title = {Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function},
	journal = {NeoplasiaNeoplasia (New York, N.Y.)},
	volume = {60},
	year = {2024},
	month = {2024/12/27},
	pages = {101117},
	address = {United States},
	abstract = {Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for 10-15 \% of breast cancer. Current treatment of high-risk early-stage TNBC includes neoadjuvant chemo-immune therapy. However, the substantial variation in immune response prompts an urgent need for new immune-targeting agents. This requires a comprehensive understanding of TNBC{\textquoteright}s tumor microenvironment. We recently demonstrated that Galectin-3 (Gal-3) binding protein/Gal-3 complex secreted by TNBC cells induces immunosuppression, through inhibiting CD45 signaling in T cells. Here, we further investigated the interaction between secreted Gal-3 and T cells in TNBC. Using CRISPR/Cas9 gene editing of the TNBC MDA-MB-231 cell-line, we obtained Gal-3 negative((neg)) clones. We studied these in an in-vitro model, co-cultured with peripheral blood mononuclear cells (PBMC) to imitate immune-tumor interaction, and in an in-vivo model, when implanted in mice. Gal-3(neg) tumors in mice had decelerated tumor growth after PBMC inoculation. In contrast, the Gal-3 positive((pos)) tumors continued growing despite PBMC inoculation, and tumor T regulatory cell (CD4/FoxP3+) infiltration increased. RNA sequencing of T cells from women with TNBC with elevated plasma levels of Gal-3 revealed significantly lower expression of oxidative phosphorylation genes than in T cells from healthy women. Similarly, in our in-vitro model, the decreased expression of oxidative phosphorylation genes and mitochondrial dysfunction resulted in a significant increase in CD8 intracellular reactive oxygen species. Consequently, T exhausted cells (CD8/PD1/Tim3/Lag3+) significantly increased in PBMC co-cultured with Gal-3(pos) TNBCs. To conclude, we revealed a novel TNBC-related Gal-3 suppressor mechanism that involved upregulation of CD4 T regulatory and of CD8 T exhausted cells.},
	keywords = {Galectin-3, Oxidative Phosphorylation, T exhausted cells, Triple negative breast cancer},
	isbn = {1476-5586},
	url = {https://pubmed.ncbi.nlm.nih.gov/39729650/},
	author = {Raiter, Annat and Barhum, Yael and Lipovetsky, Julia and Menachem, Chen and Elgavish, Sharona and Ruppo, Shmuel and Birger, Yehudit and Izraeli, Shai and Steinberg-Shemer, Orna and Yerushalmi, Rinat}
}
