Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8...

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Veröffentlicht in:Immunity (Cambridge, Mass.) Mass.), 2020-10, Vol.53 (4), p.824-839.e10
Hauptverfasser: Weulersse, Marianne, Asrir, Assia, Pichler, Andrea C., Lemaitre, Lea, Braun, Matthias, Carrié, Nadège, Joubert, Marie-Véronique, Le Moine, Marie, Do Souto, Laura, Gaud, Guillaume, Das, Indrajit, Brauns, Elisa, Scarlata, Clara M., Morandi, Elena, Sundarrajan, Ashmitha, Cuisinier, Marine, Buisson, Laure, Maheo, Sabrina, Kassem, Sahar, Agesta, Arantxa, Pérès, Michaël, Verhoeyen, Els, Martinez, Alejandra, Mazieres, Julien, Dupré, Loïc, Gossye, Thomas, Pancaldi, Vera, Guillerey, Camille, Ayyoub, Maha, Dejean, Anne S., Saoudi, Abdelhadi, Goriely, Stanislas, Avet-Loiseau, Hervé, Bald, Tobias, Smyth, Mark J., Martinet, Ludovic
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Sprache:eng
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Zusammenfassung:CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226−/− mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy. [Display omitted] •TCR signaling and CD8+ T effector program are altered by the absence of CD226•Dysfunctional CD226neg CD8+ TILs accumulate in human and mouse tumors•Eomes overexpression is involved in CD226 loss by CD8+ TILs•CD226 loss limits the efficacy of immune checkpoint blockade and CD137 agonists. Through complementary approaches, involving cancer patients’ samples and relevant mouse tumor models, Weulersse et al. reveal that CD8+ T cells in the tumor microenvironment lose expression of the activating receptor CD226 (DNAM-1) in a manner that is Eomes dependent. CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2020.09.006