CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells
| Autor: | André Veillette, Indrajit Das, Sophie Krumeich, Oltin T Pop, Jason Madore, Kyohei Nakamura, Lukas Flatz, Richard A. Scolyer, Sally Pearson, Brodie Quine, Matthias Braun, Rui Li, Brett G.M. Hughes, Andreas Möller, Touraj Taheri, Maike Effern, Sunyoung Ham, Glen Kristiansen, Sandra E. Nicholson, Ailin Lepletier, Ashmitha Sundarrajan, Martin D. Batstone, Dillon Corvino, Lizeth G. Meza Guzman, Kunlun Li, Amelia Roman Aguilera, Ludovic Martinet, Elizabeth Ahern, Nazhifah Salim, Maria Villancanas Jorge, Dimo Dietrich, Luize G. Lima, Frank Vari, Ashwini Raghavendra, Mika Casey, Jennifer Landsberg, Robert J. Johnston, Gabrielle Kelly, James S. Wilmott, Mark J. Smyth, Matthias Geyer, Eun Y. Seo, Georgina V. Long, Tobias Bald, Sebastien Jacquelin, Kimberley Stannard, William C. Dougall, Lambros T. Koufariotis, Michael Hölzel |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte Male 0301 basic medicine Adoptive cell transfer medicine.medical_treatment CD226 Immunology chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Biology Jurkat cells Cell Line Jurkat Cells Mice 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Cancer immunotherapy Cell Line Tumor medicine Animals Humans Immunology and Allergy Cytotoxic T cell Immune Checkpoint Inhibitors Melanoma Immunotherapy Immune checkpoint Mice Inbred C57BL HEK293 Cells 030104 developmental biology Infectious Diseases 030220 oncology & carcinogenesis Cancer research Receptors Virus Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Immunity. 53:805-823.e15 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2020.09.010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|