Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes

Jingjing Zhu, Céline G. Powis de Tenbossche, Stefania Cané, Didier Colau, Nicolas van Baren, Christophe Lurquin, Anne-Marie Schmitt-Verhulst, Peter Liljeström, Catherine Uyttenhove and Benoit J. Van den Eynde ()
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Jingjing Zhu: Ludwig Institute for Cancer Research
Céline G. Powis de Tenbossche: Ludwig Institute for Cancer Research
Stefania Cané: Ludwig Institute for Cancer Research
Didier Colau: Ludwig Institute for Cancer Research
Nicolas van Baren: Ludwig Institute for Cancer Research
Christophe Lurquin: Ludwig Institute for Cancer Research
Anne-Marie Schmitt-Verhulst: Aix Marseille Université, Inserm, CNRS
Peter Liljeström: Karolinska Institutet
Catherine Uyttenhove: Ludwig Institute for Cancer Research
Benoit J. Van den Eynde: Ludwig Institute for Cancer Research

Nature Communications, 2017, vol. 8, issue 1, 1-15

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.

Date: 2017
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DOI: 10.1038/s41467-017-00784-1

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