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

Assia Asrir (1) , Claire Tardiveau (1) , Juliette Coudert (1) , Robin Laffont (1) , Lucas Blanchard (1) , Elisabeth Bellard (1) , Krystle Veerman (1) , Sarah Bettini (1) , Fanny Lafouresse (1) , Estefania Vina (1) , Dorian Tarroux (1) , Severine Roy (2) , Isabelle Girault (2) , Irma Molinaro (3) , Frédéric Martins (4, 5) , Jean-Yves Scoazec (2, 6) , Nathalie Ortega (1) , Caroline Robert (2, 7) , Jean-Philippe Girard (1)

1 IPBS - Institut de pharmacologie et de biologie structurale
2 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
3 Département de biologie et pathologie médicales [Gustave Roussy]
4 UPS/Inserm U1297 - I2MC - Institut des Maladies Métaboliques et Casdiovasculaires
5 GET - Plateforme Génome & Transcriptome
6 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
7 Université Paris-Saclay

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.

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

Domaines: Immunologie; Cancer

Assia Asrir, Claire Tardiveau, Juliette Coudert, Robin Laffont, Lucas Blanchard, et al.. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell, In press, 17 p. ⟨10.1016/j.ccell.2022.01.002⟩. ⟨hal-03576428⟩