Weulersse, Asrir, and Pichler et al. showed that TCR-stimulated human CD226(DNAM-1)-CD8+ T cells demonstrated reduced TCR signaling, LFA-1 activation, proliferation and effector function; and enrichment of resting T cell, Treg cell, and TGFβ signaling genes. Re-expressing CD226 restored function. Hyporesponsive CD226- CD8+ TILs amassed in human and mouse tumors and correlated with worse clinical outcomes. Anti-PD-1 did not restore CD226- TIL responses ex vivo or antitumor responses in Cd226-/- mice. Agonizing 4-1BB induced the transcription factor Eomes to enable CD226- CD8+ T cell expansion and limit anti-murine tumor effects in vivo.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Cancer Research Center of Toulouse (CRCT), Institut National de la Sante ́ et de la Recherche Me ́ dicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS)
Author Info: (1) Cancer Research Center of Toulouse (CRCT), Institut National de la Sante ́ et de la Recherche Me ́ dicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Universite Paul Sabatier (UPS), Toulouse, France (2) QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (3) Institut Universitaire du Cancer, CHU Toulouse, France (4) UCR-I (ULB Centre for Research in Immunology), Universite Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, 6041 Belgium (5) Centre de physiopathologie de Toulouse Purpan (CPTP), INSERM UMR 1043, CNRS UMR 5282, UPS, Toulouse, France (6) Universite Cote d’Azur, INSERM, C3M, Nice, France (7) CIRI, Universite de Lyon, INSERM U1111, ENS de Lyon, CNRS UMR 5308, Lyon, France (8) Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria (9) Barcelona Supercomputing Center, Barcelona, Spain (10) These authors contributed equally (11) Lead Contact
*Correspondence: ludovic.martinet@inserm.fr
