Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Zhu, Jingjing; Powis de Tenbossche, Céline; Cané, Stefania; Colau, Didier; van Baren, Nicolas; Lurquin, Christophe; Schmitt-Verhulst, Anne-Marie; Liljeström, Peter; Uyttenhove, Catherine; Van den Eynde, Benoit
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 15
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-00784-1
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8+ T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway. Cancer immunotherapy is ineffective in a subset of patients. Here the authors show that, in a mouse model of melanoma, resistance to immune checkpoint inhibitors relies on loss of tumor-specific T cells through FasL-mediated apoptosis triggered by polymorphonuclear-myeloid-derived suppressor cells.