Zhu et al. created an autochthonous, inducible melanoma mouse model (TiRP), which, similar to many human melanomas, is resistant to immunotherapy, including adoptive cell therapy (ACT). The resistance mechanism involves apoptosis of tumor-infiltrating CD8+ T cells via FasL expression on the polymorphonuclear myeloid-derived suppressor cells, which are enriched in TiRP tumors. Blocking FasL improved the anti-tumor response of ACT in TiRP tumors and synergized with checkpoint blockade in transplanted tumors.
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.
Author Info: (1) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. Walloon Excellence in Life Scie
Author Info: (1) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. Walloon Excellence in Life Sciences and Biotechnology, Brussels, B-1200, Belgium. (2) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. (3) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. Walloon Excellence in Life Sciences and Biotechnology, Brussels, B-1200, Belgium. (4) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. (5) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. (6) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. (7) Centre d'Immunologie de Marseille-Luminy, Aix Marseille Universite, Inserm, CNRS, Marseille, France. (8) Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, SE-17177, Sweden. (9) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. (10) Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. benoit.vandeneynde@bru.licr.org. de Duve Institute, Universite Catholique de Louvain, Brussels, B-1200, Belgium. benoit.vandeneynde@bru.licr.org. Walloon Excellence in Life Sciences and Biotechnology, Brussels, B-1200, Belgium. benoit.vandeneynde@bru.licr.org.
