Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy
2022
Asrir, Assia | Tardiveau, Claire | Coudert, Juliette | Laffont, Robin | Blanchard, Lucas | Bellard, Elisabeth | Veerman, Krystle | Bettini, Sarah | Lafouresse, Fanny | Vina, Estefania | Tarroux, Dorian | Roy, Severine | Girault, Isabelle | Molinaro, Irma | Martins, Frédéric | Scoazec, Jean-Yves | Ortega, Nathalie | Robert, Caroline | Girard, Jean-Philippe
International audience
Показать больше [+] Меньше [-]Английский. 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.
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