Government of the United States of America - National Institute of Allergy and Infectious Diseases; University of Toulouse 3, Paul Sabatier University - Cancer Research Center of Toulouse (CRCT)
University of Toulouse 3, Paul Sabatier University - Cancer Research Center of Toulouse (CRCT); Université de Toulouse - Centre de Physiopathologie de Toulouse Purpan (CPTP)
CD137 (4-1BB) activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immunosurveillance remain to be addressed. Here, we found that CD137 agonists rapidly induced CD8+ T cell chromatin remodeling and expression of exhausted T cell (Tex) specific genes. T cell-intrinsic, TCR independent, CD137 signaling involving the RelA and cRel NF-kB subunits stimulated the expansion of Tex cells characterized by the expression of multiple immune checkpoints (PD1, Tim3, Tigit) and reduced effector functions. Conversely, T cell-specific CD137 deletion limited the accumulation of Tex cells in different tumor mouse models. Yet, CD137-deficient CD8+ T cells failed to persist in tumors resulting in higher tumor burden in T cell-specific CD137-deficient mice. Understanding the cellular process that drive T cell dysfunction has crucial implications for the treatment of cancer and infectious diseases. Thus, this study, that uncovers the importance of CD137 signaling in T cell exhaustion program, could have broad applications for immunotherapy.
Funding Information: This study has been partially supported through the grant EUR CARe N°ANR-18-EURE-0003 in the framework of the Programme des Investissements d'Avenir.
Declaration of Interests: The authors declare no conflict of interest.
Ethics Approval Statement: Animal experiments were conducted and approved by the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (APAFIS#5614-20 16060815487810 v4) and are in compliance with the French regulations on care and protection of laboratory animals.
Keywords: CD8+ T lymphocytes, Activation receptor, T cell exhaustion, Immunotherapy, tumor immune escape, immune checkpoint blockade.
Pichler, Andrea Charlotte and Carrié, Nadège and Voisin, Allison and Ghazali, Samira and Lucca, Liliana and Tosolini, Marie and Cuisinier, Marine and Do Souto, Laura and Ekren, Rüçhan and Blanquart, Eve and Lemaitre, Lea and Feliu, Virginie and Joubert, Marie-Véronique and Mazzotti, Céline and Guillerey, Camille and Watts, Tania and Salomon, Benoit and Joffre, Olivier and Grinberg-Bleyer, Yenkel and Avet-Loiseau, Hervé and Martinet, Ludovic, CD137 (4-1BB) Signaling Drives a TcR-Independent Exhaustion Program in CD8 T Cells. Available at SSRN: https://ssrn.com/abstract=4163142 or http://dx.doi.org/10.2139/ssrn.4163142
This version of the paper has not been formally peer reviewed.