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    Regulation and immunoregulatory properties of the phenylalanine oxidase IL4I1 in melanoma, team A Prevost-Blondel



    Immunoregulatory properties of NOS2 and IL4I1 at the early stage of melanoma development



    Principal investigator: Armelle Prévost-Blondel

    Contact : – Phone: +33 1 40 51 65 24



    Melanoma is a cancer characterized by the uncontrolled growth of melanocytes. Metastatic melanoma occurs when cancer cells disseminate beyond the surface of the skin to other organs such as lymph nodes, lungs and brain. The primary tumor is mostly curable when treated in its early stage, but metastatic melanoma is one of the most aggressive forms of cancer. Melanoma is an “immunogenic” cancer: 1) It may regress spontaneously and areas of histologic regression are mainly enriched in T lymphocytes. 2) A higher incidence of melanoma has been evidenced in organ transplant patients receiving immunosuppressive therapy. 3) Clinical studies have shown an association between autoimmunity and survival in patients with resected melanoma. Immune modulation strategies have been conducted over the last decades, but until recently, no randomized clinical trial showed an overall survival difference in patients with advanced melanoma. As noticed in Science, cancer immunotherapy was the breakthrough of the year 2013. Indeed, anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) and anti-PD-1 (programmed death receptor-1) treatments have been approved by the U.S. FDA for metastatic melanoma in 2011 and 2014 respectively. In particular, our aim is to study how NOS2 and IL4I1, two enzymes invoved in the metabolism of arginine and phenylalanine respectively, regulate the melanoma specific immune response. This project is based on our recent data providing new evidences on their contribution in tumor escape. Identification of new targets is crucial to understand the complex interplay between tumor and host microenvironment, as well as for the development of innovative anti-tumor therapies.


    The team


    Marie-Françoise Avril, Dermatology department of the Cochin Hospital (PU-PH), Renée Lengagne, engineer assistant (CNRS), Jan Philipp Ramspott, MD-PhD student (ERASMUS from Germany), Fériel Bekkat, PhD student and Master 2 students are involved in this research program.

    Applications are invited for a full-time post-doctoral position in Immunology (12 month contract from INCA with possibility of extension). The fundamental and translational project aims to elucidate the IL4I1-dependent-protumoral mechanisms in melanoma. It relies on multiple up-to-date technical approaches such as cell sorting, laser microdissection and RNA-seq analyses, combined with in vivo monitoring of melanoma development in models set up by the team.


    Research interests

    Our aim is to investigate how NOS2 and IL4I1, involved in amino acid metabolism, contribute to the tumor progression. We explore their impact on the immune response at the earliest step of melanoma development. Our research program integrate knowledge coming from the analysis of interactions between melanoma and its microenvironment obtained from our experimental mouse models and from tissue samples of melanoma patients. Our study will provide basic data on the immunosuppressive properties of IL4I1 and support a scientific rationale to develop therapeutic approaches and improve the efficacy of current therapies in patients with metastatic disease.

    The IL4I1 project benefits of our strong collaboration with Drs Flavia Castellano and Valérie Molinier- Frenkel (Institut de Recherche Biomédicale de Mondor, Créteil). Our program is developed in close collaboration with the department of Dermatology (Pr. Marie-Françoise Avril, Cochin Hospital) and Pathology (Pr. Benoit Terris, Cochin Hospital and Pr. Anne Salomon, Curie Hospital) to favor an efficient transfer from basic research to the study of melanoma in patients.


    Recent advances (2010-2018) – To gain insight into the role of immune cells and their relationships at different stages of the tumor development, we set up a model of spontaneous melanoma (RET mice) in which the primary tumor disseminates early, but remains dormant for several weeks. As observed in the human melanoma pathology, a significant proportion of RET mice spontaneously develops a vitiligo associated with a clinical benefit (Lengagne, Cancer Res., 2004; Pommier, PNAS, 2013).

    In RET mice, we have shown that : 1) CD8+ T cells control visceral metastasis spreading by maintaining the dormancy of disseminated tumor cells (Lengagne, J. Immunol., 2008; Eyles, J. Clin. Invest., 2010). 2) T cells favor cancer development by promoting the pro-tumor properties of M2 type macrophages within cutaneous metastases that, in turn, inhibit tumor specific T cells (Lengagne, Plos One, 2011).  3) Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), the most abundant immune cells infiltrating the primary tumor, are involved in tumor cell dissemination (Toh, Plos Biology, 2011). 4) Inflammatory monocytes/DCs play a key role in controlling tumor-cell dissemination that can be counteracted by regulatory T cells (Pommier, PNAS, 2013). In collaboration with Lionel Apetoh (Centre GF Leclerc, Dijon), we showed that injection of IL-1β induced tumor specific Th9 cells into RET mice delayed more efficiently than Th9 cells the tumor development, highlighting their high anti-tumor property in the context of T cell based therapy (Vegran, Nat. Immunol., 2014).

    More recently we initiated a study aiming to explore the role of NOS2 and IL4I1 in the context of melanoma. Unexpectedly, we found that NOS2 supports IL-17 production by gamma delta T cells leading to the recruitment of PMN-MDSC and metastasis formation in Ret mice (Douguet, OncoImmunology, 2016 and Douguet, OncoImmunology, 2018). In collaboration with Flavia Castellano and Valérie Molinier-Frenkel, we found in a model of tumor cell transplantation that IL4I1 expressed by B16 melanoma cells improves tumor incidence by inhibiting tumor specific CD8+ T cells (Lasoudris, Eur. J. Immunol., 2011) and that IL4I1, mainly expressed by myeloid cells in Ret mice, shapes the composition of immune cells in the primary tumor (Bod, OncoImmunology, 2017). These investigations also allowed us to highlight new roles at steady state of NOS2 (Douguet, Plos One, 2016) and IL4I1 (Bod, J Immunol 2018, study led in collaboration with Dr. Yolande Richard).

    In primary tumors of melanoma patients (Cochin Hospital), we have highlighted for the first time NOS2 expressing gamma delta T cells (Douguet, OncoImmunology, 2016). We have detected IL4I1 expression in situ in most of primary cutaneous melanoma that may be relevant to predict prognosis. Interestingly, the proportion of IL4I1+ cells correlates negatively with the presence of cytotoxic CD8+ T cells and positively with the presence of regulatory T cells (Ramspott, J. Invest. Dermatol., in press). Collectively, our findings strengthen the rationale for therapeutic targeting of NOS2 and IL4I1 as key immune regulators.


    Main publications from 2013

    • Ramspott JP, Bekkat F, Bod L, Maryline Favier M, Terris B, Salomon A, Djerroudi L, Zaenker KS, Richard Y, Molinier-Frenkel V, Castellano F, Avril M-F and Prévost-Blondel A. Emerging role of IL-4 induced gene 1 as a prognostic biomarker affecting the local T cell response in human cutaneous melanoma. J Invest Dermatol 138:2625-34
    • Douguet L, Bod L, Labarthe L, Lengagne R, Kato M, Couillin I & Prévost-Blondel A. Inflammation drives nitric oxide synthase 2 expression by γδ T cells and affects the balance between melanoma and vitiligo associated melanoma. Oncoimmunology 7(9):e1484979 2018  
    • Bod L, Douguet L, Auffray, C, Lengagne R, Bekkat F, Rondeau E, Molinier-Frenkel V, Castellano F, Richard Y* and Prévost-Blondel A*. IL4-induced gene 1 : a negative immune checkpoint controlling B cell differentiation and activation. J Immunol 200(3):1027-1038 *corresponding authors
    • Bod L, Lengagne R, Wroebel L, Ramspott JP, Kato M, Castellano F, Avril MF, Molinier-Frenkel V, and Prévost-Blondel A. IL4-induced gene 1 promotes tumor growth and modulates the tumor microenvironment in a spontaneous model of melanoma. Oncoimmunol 6(3):e1278331 2017
    • Douguet L, Cherfils-Vicini J, Bod L, Lengagne R, Gilson E and Prévost-Blondel A. Endogenous nitric oxide synthase 2 improves proliferation and glycolysis of γδ T cells. PLoS One. 3;11(11):e0165639. 2016.
    • Wrobel LJ, Bod L, Lengagne R, Kato M, Le Gal FA and Prévost-Blondel A. Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma. Oncotarget doi: 10.18632. 12833. 2016.
    • Douguet L, Bod L, Lengagne R, Labarthe L, Kato M, Avril MF, and Prévost-Blondel A. Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma. Oncoimmunol. 5(8):e1208878. 2016.
    • Dabbeche E, Krause L, Kato M, Prévost-Blondel A, Garchon H-J. Aggravation of tumor prognosis in RET-transgenic mice with a non-obese diabetic (NOD) genetic background tightly correlates with profound reduction of Dectin-1 expression on granulocytic myeloid cells and is prevented by germline inactivation of the type 2 nitric-oxide synthase (Nos2) gene. Oncoimmunol. 5(5):e1100793. 2015.
    • Pommier A, Audemard A,Durand A, Lengagne R, Delpoux A, Martin B, Douguet L, Le Campion A, Kato M, Avril  MF, Auffray C, Lucas B, Prevost-Blondel A. Inflammatory monocytes are potent anti-tumor effectors controlled by regulatory CD4+ T cells. PNAS. 110(32):13085-13090. 2013.


     Financial supports

    This program is supported by INCA, the French Society of Dermatology (SFD), the Comité Ligue de Paris (Ligue Nationale de Recherche sur la Cancer) and Melanoma patient ‘funding.



    We also recently got fundings from SILAB-Jean Paufique private foundation, Fondation ARC pour la Recherche sur le Cancer, the Comité Ligue de Paris and INCA.



    Armelle Prévost-Blondel is a member of the SIRIC (CARPEM, A cancer research network) that gathered Scientists and clinicians from Cochin and HEGP hospitals.







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