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.
Congratulations to Malvina Seradj who received a grant from ARC Foundation for Cancer Research in May 2023.
A huge thank you to the ARC Foundation for support. This will allow Malvina to pursue her thesis project on the impact of IL4I1 on the functions of macrophages associated with melanoma.
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.
References: Main publications
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. PMID: 34026337
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. PMID: 31330829
Prévost-Blondel A, Richard Y. IL4-induced gene 1 as an emerging regulator of B-cell biology and its role in cutaneous melanoma? Crit Rev Immunol. 39(1):39-57. 2019. PMID: 31679193
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(12):2625-2634. 2018. PMID: 30048651
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. PMID: 29288206
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. PMID: 28405502
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. PMID: 21469114
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. PMID: 27812136
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. PMID: 27622078
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. PMID: 21346771
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. PMID: 21408177
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. PMID: 21654834
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. PMID: 11857412
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. PMID: 23878221
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. 9(9):e1001162. 2011. PMID: 21980263
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. PMID: 21633700
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. PMID: 20501944
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. PMID: 18097012
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 Res. 64:1496-1501. 2004. PMID: 14973052
Collaborations on melanoma
Canali MM, Guyot M, Simon T, Daoudlarian D, Chabry J, Panzolini C, Petit-Paitel A, Hypolite N, Nicolas S, Bourdely P, Schmid-Antomarchi H, Schmid-Alliana A, Soria J, Karimdjee Soilihi B, Hofman P, Prevost-Blondel A, Kato M, Mougneau E, Glaichenhaus N, Blancou P. Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling. Cancer Cell Int. 23(1):15. 2023. PMID 36726173
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 Res. 29(10):846-861. 2019. PMID: 31481761
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. Nat Immunol. 15(8):758-66. 2014. PMID: 24973819
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 Res. 72(11):2757-67. 2012. PMID: 22427351
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. PMID: 22291187
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 Res. 71(16):5393-5399. 2011. PMID: 21724589
- Stéphanie Graff-Dubois, former Post-doctoral fellow Cancéropole (2006-2007) is Professor in Immunology at Sorbonne University
- Nadège Bercovici, former Post-doctoral fellow INSERM (2012-2015) is full time researcher CRCN at CNRS.
- Arnaud Pommier. former PhD student (2009-2012) is engineer, University of Reims.
- Fany Blanc, former Post-doctoral fellow INCA (2012-2015), is engineer, INRA Jouy en Josas.
- Laetitia Douguet, former Master and PhD student (2010-2015) is Senior scientist, immuno-oncology project manager, TheraVectys
- Lloyd Bod, former Master, PhD student and Post-doctoral fellow (2012-2017) is Professor assistant, Team leader at Harvard Medical School (Boston).
- Jan-Philipp Ramspott, former ERASMUS MD student (2015-2016) is MD, Department of General, Visceral and Transplant Surgery, Hospital Münster, Münster. (Germany).
- Fériel Bekkat, former Master and PhD student (2017-2021). Consultant in health innovation, Paris
- Samantha Chew, former Post-doctoral fellow INCA (2019-2021).