Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer
| Autor: | Guillaume Labrousse, Julie Tenet, Hervé Prats, Justine Noujarède, Stéphanie Delmas, Bruno Ségui, Maud Chusseau, Thomas Farge, Elie Marcheteau, Florence Dalenc, Caroline Imbert, Florence Cabon, Camille Franchet, Céline Colacios, Michaël Pérès, Raphaëlle Duprez-Paumier |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Angiogenesis medicine.medical_treatment THBS1 Article Metastasis TSP1 angiogenesis Thrombospondin 1 medicine metastasis RC254-282 Triple-negative breast cancer biology Tumor-infiltrating lymphocytes business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunotherapy Transforming growth factor beta medicine.disease Primary tumor Oncology tumor-infiltrating lymphocytes Cancer research biology.protein immunotherapy business |
| Zdroj: | Cancers Cancers, Vol 13, Iss 4059, p 4059 (2021) Volume 13 Issue 16 |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Triple-negative breast cancer (TNBC) is associated with a poor prognosis, and the development of better therapeutic strategies is required. Herein, we investigated the role of the anti-angiogenic thrombospondin-1 (TSP1) in TNBC. TSP1 expression in tumor biopsies from TNBC patients was associated with a bad prognosis and a weak content of tumor-infiltrating lymphocytes (TILs). In the 4T1 mouse TNBC model, TSP1 knockdown reduced TGF-β activation and enhanced the content of TILs. Moreover, TSP1 knockdown decreased lung metastasis in syngeneic Balb/c immunocompetent mice but not in immunodeficient nude mice. Finally, TSP1 knockdown enhanced anti-PD-1 immunotherapy efficacy. Thus, targeting TSP1 may be considered as a putative therapeutic strategy in TNBC in combination with immunotherapy. Abstract Triple-negative breast cancer (TNBC) is notoriously aggressive with a high metastatic potential, and targeted therapies are lacking. Using transcriptomic and histologic analysis of TNBC samples, we found that a high expression of thrombospondin-1 (TSP1), a potent endogenous inhibitor of angiogenesis and an activator of latent transforming growth factor beta (TGF-β), is associated with (i) gene signatures of epithelial–mesenchymal transition and TGF-β signaling, (ii) metastasis and (iii) a reduced survival in TNBC patients. In contrast, in tumors expressing low levels of TSP1, gene signatures of interferon gamma (IFN-γ) signaling and lymphocyte activation were enriched. In TNBC biopsies, TSP1 expression inversely correlated with the CD8+ tumor-infiltrating lymphocytes (TILs) content. In the 4T1 metastatic mouse model of TNBC, TSP1 silencing did not affect primary tumor development but, strikingly, impaired metastasis in immunocompetent but not in immunodeficient nude mice. Moreover, TSP1 knockdown increased tumor vascularization and T lymphocyte infiltration and decreased TGF-β activation in immunocompetent mice. Noteworthy was the finding that TSP1 knockdown increased CD8+ TILs and their programmed cell death 1 (PD-1) expression and sensitized 4T1 tumors to anti-PD-1 therapy. TSP1 inhibition might thus represent an innovative targeted approach to impair TGF-β activation and breast cancer cell metastasis and improve lymphocyte infiltration in tumors, and immunotherapy efficacy in TNBC. |
| Databáze: | OpenAIRE |
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