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
Cancer Cell. 2022-03-01; 40(3): 318-334.e9
DOI: 10.1016/j.ccell.2022.01.002

Asrir A(1), Tardiveau C(1), Coudert J(1), Laffont R(1), Blanchard L(1), Bellard
E(1), Veerman K(1), Bettini S(1), Lafouresse F(1), Vina E(1), Tarroux D(1), Roy
S(2), Girault I(2), Molinaro I(3), Martins F(4), Scoazec JY(5), Ortega N(1),
Robert C(6), Girard JP(7).

Author information:
(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:
.

Comment in
Cancer Cell. 2022 Mar 14;40(3):243-245. doi: 10.1016/j.ccell.2022.02.004.
Nat Rev Cancer. 2022 Apr;22(4):194. doi: 10.1038/s41568-022-00460-7.

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.

DOI: 10.1016/j.ccell.2022.01.002
PMID: 35120598 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of interests C.R. is an occasional
consultant to Bristol Myers Squibb, Roche, Amgen, Novartis, Pierre Fabre, MSD,
Sanofi, Biothera, CureVac, and Merck. All other authors have no competing
interests.