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CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 T Cells.

Immunity

Authors: Matthias Braun, Amelia Roman Aguilera, Ashmitha Sundarrajan, Dillon Corvino, Kimberley Stannard, Sophie Krumeich, Indrajit Das, Luize G Lima, Lizeth G Meza Guzman, Kunlun Li, Rui Li, Nazhifah Salim, Maria Villancanas Jorge, Sunyoung Ham, Gabrielle Kelly, Frank Vari, Ailin Lepletier, Ashwini Raghavendra, Sally Pearson, Jason Madore, Sebastien Jacquelin, Maike Effern, Brodie Quine, Lambros T Koufariotis, Mika Casey, Kyohei Nakamura, Eun Y Seo, Michael Hölzel, Matthias Geyer, Glen Kristiansen, Touraj Taheri, Elizabeth Ahern, Brett G M Hughes, James S Wilmott, Georgina V Long, Richard A Scolyer, Martin D Batstone, Jennifer Landsberg, Dimo Dietrich, Oltin T Pop, Lukas Flatz, William C Dougall, André Veillette, Sandra E Nicholson, Andreas Möller, Robert J Johnston, Ludovic Martinet, Mark J Smyth, Tobias Bald

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 CD226 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, CD226CD8 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.

Copyright © 2020 Elsevier Inc. All rights reserved.

PMID: 33053330

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