Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

Assia Asrir, Claire Tardiveau, Juliette Coudert, Robin Laffont, Lucas Blanchard, Elisabeth Bellard, Krystle Veerman, Sarah Bettini, Fanny Lafouresse, Estefania Vina, Dorian Tarroux, Severine Roy, Isabelle Girault, Irma Molinaro, Frédéric Martins, Jean Yves Scoazec, Nathalie Ortega, Caroline Robert, Jean Philippe Girard

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    140 Citations (Scopus)

    Abstract

    Recruitment of lymphocytes into tumors is critical for anti-tumor immunity and efficacious immunotherapy. We show in murine models that tumor-associated high endothelial venules (TA-HEVs) are major sites of lymphocyte entry into tumors at baseline and upon treatment with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB). TA-HEV endothelial cells (TA-HECs) derive from post-capillary venules, co-express MECA-79+ HEV sialomucins and E/P-selectins, and are associated with homing and infiltration into tumors of various T cell subsets. Intravital microscopy further shows that TA-HEVs are the main sites of lymphocyte arrest and extravasation into ICB-treated tumors. Increasing TA-HEC frequency and maturation increases the proportion of tumor-infiltrating stem-like CD8+ T cells, and ameliorates ICB efficacy. Analysis of tumor biopsies from 93 patients with metastatic melanoma reveals that TA-HEVs are predictive of better response and survival upon treatment with anti-PD-1/anti-CTLA-4 combination. These studies provide critical insights into the mechanisms governing lymphocyte trafficking in cancer immunity and immunotherapy.

    Original languageEnglish
    Pages (from-to)318-334.e9
    JournalCancer Cell
    Volume40
    Issue number3
    DOIs
    Publication statusPublished - 14 Mar 2022

    Keywords

    • CD8 T cells
    • CTLA-4
    • HEV
    • PD-1
    • cancer immunotherapy
    • high endothelial venule
    • immune checkpoint blockade
    • lymphocyte trafficking
    • tumor blood vessels
    • tumor immunology
    • tumor-infiltrating lymphocytes

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