title: IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma.
abstract: Amino acid catabolizing enzymes emerged as a crucial mechanism used by tumors to dampen immune responses. The L-phenylalanine oxidase IL-4 induced gene 1 (IL4I1) is expressed by tumor-associated myeloid cells of most solid tumors, including melanoma. We previously provided the only evidence that IL4I1 accelerates tumor growth by limiting the CD8+T cell mediated immune response, in a mouse model of melanoma cell transplantation. Here, we explored the role of IL4I1 in Ret mice, a spontaneous model of melanoma. We found that IL4I1 was expressed by CD11b+myeloid cells and that its activity correlated with disease aggressiveness. IL4I1 did not enhance tumor cell proliferation or angiogenesis, but orchestrated the remodeling of the immune compartment within the primary tumor. Indeed, the inactivation of IL4I1 limited the recruitment of polymorphonuclear myeloid-derived suppressor cells and enhanced the infiltration by Th1 and cytotoxic T cells, thus delaying tumor development and metastatic dissemination. Accordingly, human primary melanomas that were poorly infiltrated by IL4I1+cells exhibited a higher density of CD8+T cells. Collectively, our findings strengthen the rationale for therapeutic targeting of IL4I1 as one of the key immune regulators.
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Bod
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Lengagne
authors.affiliation: Hôpitaux Universitaires de Genève , Genève, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Wrobel
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Ramspott
authors.affiliation: Nagoya University Graduate School of Medicine , Nagoya, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; APHP, Hôpital Cochin, Paris, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.affiliation: INSERM, U955, Equipe 09, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Hôpital H. Mondor - A. Chenevier, Plateforme de Ressources Biologiques, Créteil, France.
authors.forename: Flavia
authors.initials: F
authors.lastname: Castellano
authors.affiliation: INSERM, U955, Equipe 09, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Hôpital H. Mondor - A. Chenevier, Service d'Immunologie Biologique, Créteil, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Molinier-Frenkel
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
keywords: CD8+ T cells; IL4I1; primary melanoma; tumor escape