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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.
Braun, Matthias; Aguilera, Amelia Roman; Sundarrajan, Ashmitha; Corvino, Dillon; Stannard, Kimberley; Krumeich, Sophie; Das, Indrajit; Lima, Luize G; Meza Guzman, Lizeth G; Li, Kunlun; Li, Rui; Salim, Nazhifah; Jorge, Maria Villancanas; Ham, Sunyoung; Kelly, Gabrielle; Vari, Frank; Lepletier, Ailin; Raghavendra, Ashwini; Pearson, Sally; Madore, Jason; Jacquelin, Sebastien; Effern, Maike; Quine, Brodie; Koufariotis, Lambros T; Casey, Mika; Nakamura, Kyohei; Seo, Eun Y; Hölzel, Michael; Geyer, Matthias; Kristiansen, Glen; Taheri, Touraj; Ahern, Elizabeth; Hughes, Brett G M; Wilmott, James S; Long, Georgina V; Scolyer, Richard A; Batstone, Martin D; Landsberg, Jennifer; Dietrich, Dimo; Pop, Oltin T; Flatz, Lukas; Dougall, William C; Veillette, André; Nicholson, Sandra E; Möller, Andreas; Johnston, Robert J; Martinet, Ludovic; Smyth, Mark J; Bald, Tobias.
Affiliation
  • Braun M; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Aguilera AR; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Sundarrajan A; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Corvino D; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Stannard K; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Krumeich S; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Das I; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Lima LG; Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Meza Guzman LG; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • Li K; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • Li R; Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada.
  • Salim N; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Jorge MV; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Ham S; Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Kelly G; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Vari F; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Lepletier A; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Raghavendra A; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Pearson S; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Madore J; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Jacquelin S; Gordon and Jessie Gilmour Leukemia Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Effern M; Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany; Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia.
  • Quine B; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Koufariotis LT; Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Casey M; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Nakamura K; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Seo EY; Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA.
  • Hölzel M; Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Geyer M; Institute of Structural Biology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Kristiansen G; Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Taheri T; Pathology Queensland, Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
  • Ahern E; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
  • Hughes BGM; Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
  • Wilmott JS; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia.
  • Long GV; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia.
  • Scolyer RA; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.
  • Batstone MD; Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
  • Landsberg J; Department of Dermatology and Allergy, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Dietrich D; Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Pop OT; Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
  • Flatz L; Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland; Department of Dermatology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
  • Dougall WC; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Veillette A; Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada; Department of Medicine, University of Montréal, Montréal, QC, Canada.
  • Nicholson SE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • Möller A; Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Johnston RJ; Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA.
  • Martinet L; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse F-31000, France.
  • Smyth MJ; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. Electronic address: mark.smyth@qimrberghofer.edu.au.
  • Bald T; Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. Electronic address: tobias.bald@qimrberghofer.edu.au.
Immunity ; 53(4): 805-823.e15, 2020 10 13.
Article in En | MEDLINE | ID: mdl-33053330
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.
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Full text: 1 Database: MEDLINE Main subject: Receptors, Virus / Antigens, Differentiation, T-Lymphocyte / CD8-Positive T-Lymphocytes Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Year: 2020 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Receptors, Virus / Antigens, Differentiation, T-Lymphocyte / CD8-Positive T-Lymphocytes Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Year: 2020 Type: Article