Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/4059 |
| _version_ | 1797524449844527104 |
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| author | Elie Marcheteau Thomas Farge Michaël Pérès Guillaume Labrousse Julie Tenet Stéphanie Delmas Maud Chusseau Raphaëlle Duprez-Paumier Camille Franchet Florence Dalenc Caroline Imbert Justine Noujarède Céline Colacios Hervé Prats Florence Cabon Bruno Ségui |
| author_facet | Elie Marcheteau Thomas Farge Michaël Pérès Guillaume Labrousse Julie Tenet Stéphanie Delmas Maud Chusseau Raphaëlle Duprez-Paumier Camille Franchet Florence Dalenc Caroline Imbert Justine Noujarède Céline Colacios Hervé Prats Florence Cabon Bruno Ségui |
| author_sort | Elie Marcheteau |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:57:34Z |
| format | Article |
| id | doaj.art-7a16f924b6eb46848f4dd78706086555 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:34Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7a16f924b6eb46848f4dd787060865552023-11-22T07:03:09ZengMDPI AGCancers2072-66942021-08-011316405910.3390/cancers13164059Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast CancerElie Marcheteau0Thomas Farge1Michaël Pérès2Guillaume Labrousse3Julie Tenet4Stéphanie Delmas5Maud Chusseau6Raphaëlle Duprez-Paumier7Camille Franchet8Florence Dalenc9Caroline Imbert10Justine Noujarède11Céline Colacios12Hervé Prats13Florence Cabon14Bruno Ségui15Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceSeleXel, 1 Place Pierre Potier, BP 50624, CEDEX 1, 31106 Toulouse, FranceSeleXel, 1 Place Pierre Potier, BP 50624, CEDEX 1, 31106 Toulouse, FranceInstitut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 Av. Irène Joliot-Curie, 31100 Toulouse, FranceInstitut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 Av. Irène Joliot-Curie, 31100 Toulouse, FranceInstitut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 Av. Irène Joliot-Curie, 31100 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CNRS UMR5071, 2 Aavenue Hubert Curien, CEDEX 1, 31047 Toulouse, FranceTriple-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.https://www.mdpi.com/2072-6694/13/16/4059THBS1TSP1angiogenesismetastasisimmunotherapytumor-infiltrating lymphocytes |
| spellingShingle | Elie Marcheteau Thomas Farge Michaël Pérès Guillaume Labrousse Julie Tenet Stéphanie Delmas Maud Chusseau Raphaëlle Duprez-Paumier Camille Franchet Florence Dalenc Caroline Imbert Justine Noujarède Céline Colacios Hervé Prats Florence Cabon Bruno Ségui Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer Cancers THBS1 TSP1 angiogenesis metastasis immunotherapy tumor-infiltrating lymphocytes |
| title | Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer |
| title_full | Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer |
| title_fullStr | Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer |
| title_full_unstemmed | Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer |
| title_short | Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer |
| title_sort | thrombospondin 1 silencing improves lymphocyte infiltration in tumors and response to anti pd 1 in triple negative breast cancer |
| topic | THBS1 TSP1 angiogenesis metastasis immunotherapy tumor-infiltrating lymphocytes |
| url | https://www.mdpi.com/2072-6694/13/16/4059 |
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