TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 7; pp. 1631 - 1648.e10
• Main Authors: Pichler, Andrea C., Carrié, Nadège, Cuisinier, Marine, Ghazali, Samira, Voisin, Alison, Axisa, Pierre-Paul, Tosolini, Marie, Mazzotti, Céline, Golec, Dominic P., Maheo, Sabrina, do Souto, Laura, Ekren, Rüçhan, Blanquart, Eve, Lemaitre, Lea, Feliu, Virginie, Joubert, Marie-Véronique, Cannons, Jennifer L., Guillerey, Camille, Avet-Loiseau, Hervé, Watts, Tania H., Salomon, Benoit L., Joffre, Olivier, Grinberg-Bleyer, Yenkel, Schwarzberg, Pamela L., Lucca, Liliana E., Martinet, Ludovic
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-07-2023; Elsevier
• Subjects: activation receptor; Adaptive immunology; Animals; CD137 (TNFRSF9, 4-1BB); CD8+ T lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; immune checkpoint blockade; Immunology; immunotherapy; Life Sciences; Mice; Neoplasms; NF-κB signaling; Receptors, Antigen, T-Cell; T cell exhaustion; tumor immune escape; Tumor Necrosis Factor Receptor Superfamily, Member 9; NF-κB signaling; activation receptor; immunotherapy; T cell exhaustion; tumor immune escape; CD8+ T lymphocytes; CD137 (TNFRSF9, 4-1BB); immune checkpoint blockade; CD8(+) T lymphocytes
• DOI: 10.1016/j.immuni.2023.06.007
• EISSN: 1097-4180
• ISSN: 1074-7613

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.
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•T cell-specific deletion of CD137 limits the presence of CD8+ Tex cells in tumors•NF-κB-dependent CD137 signaling stimulates Tex cell proliferation and differentiation•CD137 activation drives the Tox-dependent epigenetic remodeling of Tex cell genes•Anti-PD1 efficacy is improved by subsequent CD137 stimulation
Manipulating exhausted T (Tex) cells has therapeutic implications. Pichler et al. found that the activating receptor, CD137 (4-1BB), was specifically expressed by Tex cells. CD137 signaling promoted TCR-independent proliferation and terminal differentiation of Tex cells. In murine tumor models, treatment with CD137 agonists specifically after anti-PD1 therapy improves anti-tumor responses.