Team photo

Cutaneous melanoma is a public health problem that affects 8 to 10,000 people per year in France. It is considered as one of the most immunogenic solid tumors. Thus, the presence of CD8+ T cells infiltrating primary tumors correlates with a good prognosis. Recently, antibodies targeting the two T-cell inhibitory receptors CTLA-4 and PD1, aimed at restoring the function of anergic tumor-specific T cells, have revolutionized the treatment of metastatic cutaneous melanoma. However, the results in terms of overall survival and response are very variable, hence the need to deepen our understanding of the mechanisms of immune escape and to identify new actors, potential targets for adjuvant therapies.

Enzymes involved in amino acid catabolism represent privileged targets for cancer treatment. In particular, the team has demonstrated the pro-tumor role of inducible nitric oxide synthetase (iNOS) and IL-4 Induced gene 1 (IL4I1) in melanoma, reinforcing the rationale for targeting these enzymes in combinatorial therapeutic strategies (Douguet. 2016 and 2018, Bod. 2017, Ramspott. 2018, Prévost-Blondel. 2019). We are investigating how these enzymes impact the immune response during the early phase of tumor development in models of spontaneous metastatic melanoma (mice transgenic for a constitutively activated form of the human RET oncogene and with wild-type or inactivated iNOS or IL4I1 genes). We are evaluating whether IL4I1 expression is a relevant marker for the disease prognosis and/or the resistance to immunotherapy in melanoma patients in a clinical trial conducted in collaboration with clinicians from Cochin and Avicenne hospitals (ClinicalTrials.gov Identifier: NCT04253080).

In conclusion, the work of our group is fundamental to understand the complexity of the relationship between tumor cells and its immune microenvironment, and to develop new therapies for cancer patients.

Fundings

References

Main publications

IL4I1

Castellano F, Prévost-Blondel A, Cohen JL, Molinier-Frenkel V. What role for AHR activation in IL4I1-mediated immunosuppression ? Oncoimmunol. Vol.10(1), e1924500. 2021.

Puiffe ML, Dupont A, Sako N, Gatineau J, Cohen J, Mestivier D, Le Bon A, Prévost-Blondel A, Castellano F and Molinier-Frenkel V. IL4I1 accelerates the expansion of effector CD8+ T cells at the expense of memory precursors by increasing the threshold of T cell activation. Front. Immunol. 11:600012. 2020. PMID: 33343572

Molinier-Frenkel V, Prévost-Blondel A, Castellano F. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells. 20;8(7):757. 2019

Prévost-Blondel A, Richard Y. IL4-induced gene 1 as an emerging regulator of B-cell biology and its role in cutaneous melanoma? Critical Reviews in Immunology. 39(1):39-57. 2019.   

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. JID 138(12):2625-2634. 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. 2018.

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.

Lasoudris F, Cousin C, Prévost-Blondel A, Martin-Garcia N, Abd-Alsamad I, Ortonne N, Farcet JP, Castellano F, V Molinier-Frenkel. Inhibition of antitumor T-cell response and immune escape in mice associated with IL4I1 expression.  Eur. J. Immunol. 41:1629-38. 2011.

NOS2

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. Oncoimmunol. 7(9):e1484979. 2018.

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.

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.

Human melanoma

Chapon M, Randriamampita C, Maubec E, Badoual C, Fouquet S, Wang S-F, Marinho E, Farhi D, Garcette M, Jacobelli S, Rouquette A, Carlotti A, Girod A, Prévost-Blondel A, Trautmann A, Avril MF, N Bercovici. Progressive upregulation of PD1 in primary and metastatic melanoma associated with blunted TCR-signalling in infiltrating T lymphocytes. J. Invest. Dermatol. 131:1300-07. 2011.

Wang SF, Fouquet S, Chapon M, Salmon H, Regnier F, Labroquère K, Badoual C, Damotte D, Validir P, Maubec E, Barry N, Cazes A, Vieillefond A, Garcette M, Dieu-Nosjean MC, Zerbib M, Barthes F, Avril MF, Prevost-Blondel A, Randriamampita C, Trautmann A, N Bercovici. Early T cell signalling is reversibly altered in T lymphocytes infiltrating human tumors. Plos One. 6:e17621. 2011.

Nardin A, Wong WC, Tow C, Molina T, Tissier F, Audebourg A, Garcette M, Caignard A, Avril MF, Abastado JP, A Prévost-Blondel. Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions. J. Invest. Dermatol. 131(9):1896-905. 2011.

Le Gal FA, Prévost-Blondel A, Lengagne R, Bossus M, Farace F, Chaboissier A, Gras-Masse H, Guillet JG, H Gahéry-Segard. Lipopeptide-based melanoma cancer vaccine induced a strong Mart-27-35 cytotoxic T lymphocyte response in a preclinical study. Int. J. Cancer. 98:221-227. 2002.

Melanoma models: RET mice and MeLiM swine

Blanc F, A Prévost-Blondel, G Piton, E Bouguyon, J-J Leplat, F Andréoletti, G Egidy-Maskos, E Bourneuf, N Bertho,  S Vincent-Naulleau. The composition of circulating leukocytes varies with age and melanoma onset in the MeLiM pig biomedical model. Front. Immunol. 00291 eCollection. 2020.  PMID: 32180771

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.

Toh B, Wang X, Keeble J, Jing Sim W, Khoo K, Wong WC, Kato M, Prevost-Blondel A, Thiery JP, JP Abastado. Mesenchymal Transition and Dissemination of Cancer Cells is driven by Myeloid-Derived Suppressor Cells Infiltrating the Primary Tumor. PLoS Biol. Sep;9(9):e1001162. 2011.

Lengagne R, Pommier A, Caron J, Douguet L, Garcette M, Kato M, Avril MF, Abastado JP, Bercovici N, Lucas B, Prévost-Blondel A. T cells contribute to tumor progression by favoring pro-tumoral properties of intra-tumoral myeloid cells in a mouse model for spontaneous melanoma. Plos One. 6:e20235. 2011.

Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M, Tan TG, Zheng L, Ong LC,  Jin Y, Kato M, Prévost-Blondel A, Chow P, Yang H, Abastado JP. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120(6):2030-9. 2010.

Lengagne R, Graff-Dubois S, Garcette M, Renia L, Kato M, Guillet JG, Engelhard VH, Avril MF, Abastado JP, Prévost-Blondel A. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J. Immunol. 180:130-7. 2008.

Lengagne R, FA Le Gal, M Garcette, L Fiette, P Ave, M Kato, JP Briand, C Massot, I Nakashima, L Rénia, JG Guillet, A Prévost-Blondel. Spontaneous vitiligo in an animal model for human melanoma: Role of tumor-specific CD8+ T cells. Cancer Research. 64:1496-1501. 2004.

Collaborations on melanoma

Iida M, Tazaki, A, Yajima I, Yajima I, Ohgami N, Taguchi N, Goto Y, Kumasaka MY, Prévost-Blondel A, Kono M, Akiyama M, Takahashi M and Kato M. Hair graying with aging in a mice carrying oncogenic RET. Aging Cell. 19(11):e13273. 2020.  PMID: 33159498

Jacquelot N, Yamazaki T, Roberti MP, Andrews MC, Verlingue L, Ferrere G, Duong C, Becharef S, Vétizou M, Daillère R, Messaoudene M, Enot D, Stoll G, Ugel S, Marigo I, Ngiow S, Marabelle A, Prévost-Blondel A, Gaudreau PO, Gopalakrishnan V, Eggermont A, Opolon P, Klein C, Madonna G, Ascierto P, Sucker A, Schadendorf D, Smyth MJ, Soria JC, Kroemer G, Bronte V, Wargo J, and Zitvogel L. Sustained Type I IFN signaling as a mechanism of resistance to PD-1 blockade . Cell Research. 29(10):846-861. 2019.

Végran F, Berger H, Boidot R, Mignot G, Bruchard M, Dosset M, Chalmin F, Rébé C, Dérangère V, Ryffel B, Kato M, Prévost-Blondel A, Ghiringhelli F and Apetoh L. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nature Immunol. 15(8):758-66. 2014.

Terme M, Ullrich E, Aymeric L, Meinhardt K, Coudert J, Desbois François Ghiringhelli , Viaud S,Ryffel B, Yagita H, Chen L, Mecheri S,  Kaplanski G, Prévost-Blondel A, Kato M, Schultze JL, Tartour E, Kroemer G, Degli-Esposti M, Chaput N, Zitvogel, L. Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells. Cancer Research. 72(11):2757-67. 2012.

Chauvin JM, Larrieu P, Sarrabayrouse G, Prévost-Blondel A, Lengagne R, Desfrançois J, Labarriere N, Jotereau F. HLA anchor optimization of the Melan-A-HLA-A2 epitope within a long peptide is required for efficient cross-priming of human tumor-reactive T cells. J Immunol. 188(5):2102-10. 2012.

Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, Viaud S, Ryffel B, Yagita H, Kaplanski G, Prevost-Blondel A, Kato M, Schultze J, Tartour E, Kroemer G, Chaput N, Zitvogel L. IL-18 induces PD1-dependent immunosuppression in cancer. Cancer Research 71(16):5393-5399. 2011.

Actualité

Congratulations to Anna Llebaria Fabrias, who received a grant from Foundation SILAB-Jean-PAUFIQUE 2022 for her PhD project on melanoma associated microbiota.

Thanks to this Foundation who supports again a PhD student from our team.

Credits/Legende