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

Publication

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

Journal Paper/Review - Oct 13, 2020

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

Citation

Bald T, Scolyer R, Long G, Wilmott J, Hughes B, Ahern E, Taheri T, Kristiansen G, Geyer M, Hölzel M, Seo E, Batstone M, Landsberg J, Smyth M, Martinet L, Johnston R, Möller A, Nicholson S, Veillette A, Dougall W, Flatz L, Pop O, Dietrich D, Nakamura K, Casey M, Koufariotis L, Li R, Li K, Meza Guzman L, Lima L, Das I, Krumeich S, Stannard K, Corvino D, Sundarrajan A, Aguilera A, Salim N, Jorge M, Quine B, Effern M, Jacquelin S, Madore J, Pearson S, Raghavendra A, Lepletier A, Vari F, Kelly G, Ham S, Braun M. CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 T Cells. Immunity 2020; 53:805-823.e15.

Type

Journal Paper/Review (English)

Journal

Immunity 2020; 53

Publication Date

Oct 13, 2020

Issn Electronic

1097-4180

Pages

805-823.e15

Brief description/objective

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.