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

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...

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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
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Summary:	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. [Display omitted] •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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Study conception and design, A.C.P., N.C., and L.M.; acquisition of data, A.C.P., N.C., M.C., A.V., C.M., D.P.G., S.M., L.L., V.F., M.-V.J., and C.G.; analysis and interpretation of data, A.C.P., N.C., A.V., P.-P.A., M.T., L.d.S., O.J., Y.G.-B., L.E.L., and L.M.; drafting of manuscript, A.C.P., P.L.S., L.E.L., and L.M.; critical revision and editing, A.C.P., R.E., E.B., J.L.C., H.A.-L., T.H.W., B.L.S., O.J., Y.G.-B., P.L.S., L.E.L., and L.M.; provision of key materials, T.H.W., B.L.S., P.L.S., H.A.-L., and L.M. AUTHOR CONTRIBUTIONS
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2023.06.007