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

Cancer Cell. 2022 Mar 14;40(3):318-334.e9. doi: 10.1016/j.ccell.2022.01.002. | PubMed

Assia Asrir¹, Claire Tardiveau¹, Juliette Coudert¹, Robin Laffont¹, Lucas Blanchard¹, Elisabeth Bellard¹, Krystle Veerman¹, Sarah Bettini¹, Fanny Lafouresse¹, Estefania Vina¹, Dorian Tarroux¹, Severine Roy², Isabelle Girault², Irma Molinaro³, Frédéric Martins⁴, Jean-Yves Scoazec⁵, Nathalie Ortega¹, Caroline Robert⁶, Jean-Philippe Girard⁷

1. Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
2. Department of Medicine, Gustave Roussy, Villejuif, France; INSERM U981, Gustave Roussy, Villejuif, France.
3. Department of Pathology, Gustave Roussy, Villejuif, France.
4. Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, UMR1048, INSERM, UPS, Toulouse, France; Plateforme Genome et Transcriptome, GeT, Genopole Toulouse, France.
5. INSERM U981, Gustave Roussy, Villejuif, France; Department of Pathology, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France; AMMICa, CNRS-UAR 3655 and INSERM-US23, Gustave Roussy, Villejuif, France.
6. Department of Medicine, Gustave Roussy, Villejuif, France; INSERM U981, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France.
7. Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address: jean-philippe.girard@ipbs.fr.

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.

Presented By Jean-philippe Girard | ORCID iD