Jean-Philippe Girard, Directeur de Recherche INSERM

CNRS Silver Medal 2013,
Team leader “Biologie Vasculaire: Cellules endothéliales dans l’Immunité, l’Inflammation et le Cancer”
IPBS-CNRS (Institut de pharmacologie et de biologie structurale), Université de Toulouse, Toulouse, France.

High endothelial venules (HEVs) : specialized blood vessels for lymphocyte entry in tumors during cancer immunotherapy

Conference in English.
—

Tuesday, December 10, 2024, 2:30 p.m.

conference room BBS (Bordeaux, Biologie Santé) 2 rue Dr Hoffmann Martinot – Site Carreire Université de Bordeaux

Keywords

Tumor microenvironnement, Tumor-infiltrating lymphocytes, Cancer immunotherapy

Abstract

Immunotherapy, a therapeutic strategy aimed at increasing the activity of the immune system, has revolutionized cancer treatment over the past decade. A better understanding of how this therapeutic approach works, and more particularly how killer lymphocytes access tumors during immunotherapy, could improve the efficacy of the treatments. We recently discovered the essential role played in this process by specialized blood vessels known as tumor-associated high endothelial venules (TA-HEVs) (Asrir* et al. Cancer Cell 2022). TA-HEVs share important phenotypic and functional characteristics with HEVs in lymph nodes and other lymphoid organs (Moussion and Girard, Nature 2011 ; Girard et al, Nature Rev Immunol 2012). For the first time, we were able to film the lymphocytes infiltrating TA-HEV walls to enter the tumors. We found that increasing the proportion of TA-HEVs in a tumor improves the infiltration of stem-like CD8+ T cells, the efficacy of the immunotherapy and leads to the eradication of the tumors. Finally, we showed that the likelihood of recovery of metastatic melanoma patients treated with anti-PD-1 plus anti-CTLA-4 immunotherapy is increased when a large number of TA-HEVs are present in tumors. Together our results suggest that increasing the density of TA-HEVs in human tumors could increase lymphocyte infiltration, making immunotherapy effective in a greater number of patients.

References

Asrir, A.*, Tardiveau; C.*, Coudert, J.*, Laffont, R.*, Blanchard, L.*, Bellard, E., Veerman, K., Bettini, S., Lafouresse, F., Vina, E., Tarroux, D., Roy, S., Girault, I., Molinaro, I., Martins, F., Scoazec, J.Y., Ortega, N., Robert, C. and Girard, J.P. (2022) Tumor-associated HEVs mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell, 40:318-334 (article sélectionné dans ‘Best of Cancer Cell 2022’, ‘Highly cited article’ du Web of Science; 157 citations dans Google Scholar).

Girard, J.P., Moussion, C., and Forster, R. (2012). HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12, 762-773.

Moussion, C., and Girard, J.P. (2011). Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479, 542-546.

Biosketch

Jean-Philippe Girard (PhD) currently holds a position of Senior Research Director at INSERM (French NIH) at IPBS-CNRS, a large Research Center from the CNRS and the University of Toulouse (France). He received his Ph.D. in Molecular Biology from the University of Toulouse and did his postdoctoral training in Immunology and Vascular Biology at Harvard Medical School (USA) with Pr Tim Springer. Jean-Philippe Girard’s research focuses on the role of high endothelial venules (HEVs) and interleukin-33 (IL-33) in immunity, inflammation and cancer. He discovered the alarmin cytokine IL-33 as a nuclear factor of HEV (NF-HEV). HEV blood vessels are portals of entry for lymphocytes into lymphoid organs (Moussion and Girard, Nature 2011; Girard et al, Nature Rev Immunol 2012). He showed that blood vessels with HEV characteristics designated tumor-associated HEVs are the main sites of lymphocyte entry into tumors, and are associated with response to immune checkpoint blockade (Asrir* et al Cancer Cell 2022). Dr. Girard is a Highly Cited Researcher in Immunology according to the Web of Science (HCR Index 2023). He received several Scientific Prizes for his work, including the CNRS Silver Medal (2103), and Prizes from the National Academy of Sciences (2012), the National Academy of Medecine (2013), ‘Fondation pour la Recherche Médicale’ (2016), ‘Fondation de France’ (2018) and ‘Fondation ARC’ (2024).

Jean-Philippe Girard is invited by Team 9 Sarcotarget to sit on the jury for Florent Peyraud’s thesis defense on the same day.