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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

    Author(s)
    Braun, M
    Aguilera, AR
    Sundarrajan, A
    Corvino, D
    Stannard, K
    Krumeich, S
    Das, I
    Lima, LG
    Meza Guzman, LG
    Li, K
    Li, R
    Salim, N
    Jorge, MV
    Lepletier, A
    et al.
    Griffith University Author(s)
    Lepletier de Oliveira, Ailin
    Year published
    2020
    Metadata
    Show full item record
    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 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 ...
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    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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    Journal Title
    Immunity
    Volume
    53
    Issue
    4
    DOI
    https://doi.org/10.1016/j.immuni.2020.09.010
    Subject
    Immunology
    CBL-B
    CD155
    CD226
    DNAM-1
    HNSCC
    Publication URI
    http://hdl.handle.net/10072/402245
    Collection
    • Journal articles

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