Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function
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 a...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558624001581 |
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| author | Annat Raiter Yael Barhum Julia Lipovetsky Chen Menachem Sharona Elgavish Shmuel Ruppo Yehudit Birger Shai Izraeli Orna Steinberg-Shemer Rinat Yerushalmi |
| author_facet | Annat Raiter Yael Barhum Julia Lipovetsky Chen Menachem Sharona Elgavish Shmuel Ruppo Yehudit Birger Shai Izraeli Orna Steinberg-Shemer Rinat Yerushalmi |
| author_sort | Annat Raiter |
| collection | DOAJ |
| description | 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'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-3neg 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-3pos 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. |
| format | Article |
| id | doaj-art-1294b6836c2344c9ba6ceed97631d078 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-1294b6836c2344c9ba6ceed97631d0782025-02-03T04:16:35ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101117Galectin-3 secreted by triple-negative breast cancer cells regulates T cell functionAnnat Raiter0Yael Barhum1Julia Lipovetsky2Chen Menachem3Sharona Elgavish4Shmuel Ruppo5Yehudit Birger6Shai Izraeli7Orna Steinberg-Shemer8Rinat Yerushalmi9Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, Israel; Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel; Corresponding author at: Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Rabin Medical Center, Beilinson Campus, Petah Tikva, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, IsraelBioinformatics Unit of the I-CORE, The Hebrew University of Jerusalem, Hadassah Ein-Karem campus, Medical School Building, Jerusalem, IsraelBioinformatics Unit of the I-CORE, The Hebrew University of Jerusalem, Hadassah Ein-Karem campus, Medical School Building, Jerusalem, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, Israel; The Rina Zaizov Hematology-Oncology Division, Schneider Children Medical Center of Israel, Beilinson Campus, Petah Tikva, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, Israel; The Rina Zaizov Hematology-Oncology Division, Schneider Children Medical Center of Israel, Beilinson Campus, Petah Tikva, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, Israel; The Rina Zaizov Hematology-Oncology Division, Schneider Children Medical Center of Israel, Beilinson Campus, Petah Tikva, IsraelFelsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Tel Aviv University, Faculty of Medicine and Health Sciences, Tel Aviv, Israel; Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel; Davidoff Cancer Center, Beilinson Campus, Petah Tikva, IsraelTriple-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'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-3neg 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-3pos 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.http://www.sciencedirect.com/science/article/pii/S1476558624001581Triple negative breast cancerGalectin-3T exhausted cellsOxidative phosphorylation |
| spellingShingle | Annat Raiter Yael Barhum Julia Lipovetsky Chen Menachem Sharona Elgavish Shmuel Ruppo Yehudit Birger Shai Izraeli Orna Steinberg-Shemer Rinat Yerushalmi Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function Neoplasia: An International Journal for Oncology Research Triple negative breast cancer Galectin-3 T exhausted cells Oxidative phosphorylation |
| title | Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function |
| title_full | Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function |
| title_fullStr | Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function |
| title_full_unstemmed | Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function |
| title_short | Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function |
| title_sort | galectin 3 secreted by triple negative breast cancer cells regulates t cell function |
| topic | Triple negative breast cancer Galectin-3 T exhausted cells Oxidative phosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S1476558624001581 |
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