Endothelial cells in Immunity, Inflammation and Cancer

Our team is among the world leaders for the characterization of high endothelial venules (HEVs), portals of entry for lymphocytes into lymphoid organs, inflamed and tumor tissues, and for the study of interleukin-33 (IL-33), a nuclear alarmin from the IL-1 cytokine family that we discovered in 2003, which plays crucial roles in innate immunity and allergic inflammation. 

The very unique, long-standing and multidisciplinary expertise of our team is a key asset to study the roles of HEVs and IL-33 in immunity, inflammation and cancer.

We demonstrated that dendritic cells, which are well known for their role as antigen-presenting cells, play an unexpected and important role in the regulation of HEV differentiation and function in lymph nodes (Nature 2011). Using single-cell RNA sequencing, we revealed the cellular and spatial heterogeneity of HEVs in lymph nodes, and we identified the genes modulated after inhibition of the dialog between HEVs and dendritic cells (Cell Reports 2019). A decade ago, we discovered the frequent presence of HEV-like blood vessels in human solid tumors (designated Tumor-Associated HEVs, TA-HEVs), and their association with cytotoxic lymphocyte infiltration and favourable clinical parameters (Cancer Res 2011, 311 citations). Our study introduced a novel concept in cancer biology “Blood vessels in human tumors are not all the same and specific subsets (i.e., TA-HEVs) can contribute to tumor suppression rather than tumor growth”. Using intravital microscopy, we recently showed that TA-HEVs are major sites of lymphocyte entry into tumors during anti-tumor immune responses and cancer immunotherapy, exhibit a unique bi-functional hybrid phenotype, and are associated with better clinical response and survival of metastatic melanoma patients treated with anti-PD-1/anti-CTLA-4 cancer immunotherapy (Cancer Cell 2022). We believe that novel therapeutic strategies based on the modulation of TA-HEVs could have a major impact on antitumor immunity, response to cancer immunotherapy, and clinical outcome of cancer patients.

IL-33 is a chromatin-associated cytokine from the IL-1 family that we initially discovered as a major nuclear factor of HEV (NF-HEV) (PNAS 2007, 765 citations). We showed that IL-33 is a tissue-derived nuclear cytokine constitutively expressed to high levels in blood vessels and epithelial barrier tissues (PLoS 2008, 875 citations). We demonstrated that IL-33 functions as an alarm signal (alarmin) released upon cell damage to alert immune cells expressing the IL-33 receptor ST2 (PNAS 2009, 510 citations). These include various cell types involved in type-2 immunity and allergic inflammation such as mast cells, and group 2 innate lymphoid cells (ILC2s). We demonstrated that inflammatory proteases can generate truncated forms of IL-33 that are 30-fold more potent than the full length protein for activation of group 2 innate lymphoid cells (PNAS 2012, 389 citations; PNAS 2014). Recently, we discovered that full length IL-33 functions as a protease sensor that detects proteolytic activities associated with a large variety of environmental allergens (Nat Immunol 2018, 174 citations). An important objective of our team is to further characterize IL-33 regulation and mechanisms of action in vivo, through the use of multidisciplinary approaches.

Team members

Research Scientists

Corinne Cayrol (CNRS)
Jean-Philippe Girard (Inserm)
Emma Lefrançais (CNRS)
Nathalie Ortéga (University)

Research Engineers

Elisabeth Bellard (CNRS)
Pascale Mercier (CNRS)
Stéphane Roga (CNRS)
Clara Saint-Martin
Dorian Tarroux

Postdoctoral Fellow

Jade Hebras

PhD Students

Léa Fromont
Lucie Gelon
Jerko Ljubetic
Estefania Vina-Barrientos

Our research projects

Asrir*, Tardiveau*, Coudert*, Laffont*, Blanchard* et al. (2022) Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell

Cayrol*, Duval* et al. (2018) Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nat Immunol 

Lefrançais*, Duval* et al. (2014) Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc Natl Acad Sci USA

Martinet*, Garido* et al. (2011) Human solid tumors contain high endothelial venules (HEV): association with T and B lymphocyte infiltration and favourable prognosis in breast cancer. Cancer Res 

Moussion and Girard (2011) Dendritic cells control lymphocyte entry to lymph nodes via high endothelial venules. Nature 

Cayrol and Girard (2009) The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA 

High endothelial cells from HEVs (green) are characterized by a plump morphology and express high levels of the alarmin cytokine IL-33 (red). © Jean-Philippe Girard
Jean-Philippe Girard ranks among the world’s most cited scientists in the prestigious ‘Highly Cited Researchers’ list in 2019, 2020 and 2022, in the Immunology category.