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

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

doi:10.1016/j.immuni.2020.09.010

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

Immunity. 2020 Oct 13;53(4):805-823.e15. doi: 10.1016/j.immuni.2020.09.010.

Authors

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

Affiliations

¹ 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.
² Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
³ Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
⁴ Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
⁵ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
⁶ Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, McGill University, Montréal, QC, Canada.
⁷ Gordon and Jessie Gilmour Leukemia Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
⁸ 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.
⁹ Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
¹⁰ Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA.
¹¹ Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹² Institute of Structural Biology, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹³ Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹⁴ Pathology Queensland, Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
¹⁵ 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.
¹⁶ Royal Brisbane and Women's Hospital, University of Queensland Herston, Herston, QLD, Australia.
¹⁷ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; The University of Sydney, Central Clinical School, Sydney, NSW, Australia.
¹⁸ 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.
¹⁹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁰ Department of Dermatology and Allergy, University Hospital Bonn, University of Bonn, Bonn, Germany.
²¹ Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany.
²² Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
²³ Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland; Department of Dermatology, Kantonsspital St.Gallen, St.Gallen, Switzerland.
²⁴ 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.
²⁵ Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse F-31000, France.
²⁶ Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. Electronic address: mark.smyth@qimrberghofer.edu.au.
²⁷ Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. Electronic address: tobias.bald@qimrberghofer.edu.au.

PMID: 33053330
DOI: 10.1016/j.immuni.2020.09.010

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 CD226^hi 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.

Keywords: CBL-B; CD155; CD226; DNAM-1; HNSCC; adoptive cell transfer; cancer immunotherapy; dysfunctional CD8(+) T cells; melanoma; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Differentiation, T-Lymphocyte / immunology*
CD8-Positive T-Lymphocytes / immunology*
Cell Line
Cell Line, Tumor
HEK293 Cells
Humans
Immune Checkpoint Inhibitors / immunology
Immunotherapy / methods
Jurkat Cells
Lymphocytes, Tumor-Infiltrating / immunology
Male
Melanoma / immunology
Mice
Mice, Inbred C57BL
Receptors, Virus / immunology*

Substances

Antigens, Differentiation, T-Lymphocyte
CD226 antigen
Immune Checkpoint Inhibitors
Receptors, Virus
poliovirus receptor

Abstract

Publication types

MeSH terms

Substances

Grants and funding