| Literature DB >> 33053330 |
Matthias Braun1, Amelia Roman Aguilera2, Ashmitha Sundarrajan3, Dillon Corvino3, Kimberley Stannard1, Sophie Krumeich3, Indrajit Das2, Luize G Lima4, Lizeth G Meza Guzman5, Kunlun Li5, Rui Li6, Nazhifah Salim3, Maria Villancanas Jorge3, Sunyoung Ham4, Gabrielle Kelly2, Frank Vari2, Ailin Lepletier2, Ashwini Raghavendra2, Sally Pearson2, Jason Madore2, Sebastien Jacquelin7, Maike Effern8, Brodie Quine1, Lambros T Koufariotis9, Mika Casey2, Kyohei Nakamura2, Eun Y Seo10, Michael Hölzel11, Matthias Geyer12, Glen Kristiansen13, Touraj Taheri14, Elizabeth Ahern15, Brett G M Hughes16, James S Wilmott17, Georgina V Long18, Richard A Scolyer19, Martin D Batstone16, Jennifer Landsberg20, Dimo Dietrich21, Oltin T Pop22, Lukas Flatz23, William C Dougall2, André Veillette24, Sandra E Nicholson5, Andreas Möller4, Robert J Johnston10, Ludovic Martinet25, Mark J Smyth26, Tobias Bald27.
Abstract
The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.Entities:
Keywords: CBL-B; CD155; CD226; DNAM-1; HNSCC; adoptive cell transfer; cancer immunotherapy; dysfunctional CD8(+) T cells; melanoma; ubiquitination
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Year: 2020 PMID： 33053330 DOI： 10.1016/j.immuni.2020.09.010
Source DB: PubMed Journal: Immunity ISSN： 1074-7613 Impact factor: 43.474