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.

KEYWORDS:

• CD8⁺ T cells
• IL4I1
• primary melanoma
• tumor escape

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

L. Bod was supported by Paris V University. J-P. Ramspott was supported by a fellowship from the Claussen-Simon-Stiftung, Hamburg and an ERASMUS fellowship. This work was supported by Gefluc, Comité “Ile de France” Ligue contre le Cancer and by the Fondation ARC for cancer research. We are grateful to Y. Richard for helpful discussion, L. Douguet for critical review of the manuscript and M. Garcette for technical support. We acknowledge the Cochin cytometry and Immunobiology facility, Histology and Immunostaining facility and the Animal core facility. We thank F. Boitier, N. Kramkimel and J. Chanal for patient recruitment, the anatomopathology department of Curie Institute for the biopsies, patients who gave their consent to participate to this study, and C. Auger and D. Bourgeois from URC Paris Center who contributed to the immumela project.

Author contributions

L.B., R.L., L.W., and JP.R. did experiments; L.B., and A.P.B. designed the study with the help of V.MF., F.C. and M.F.A. L.B., V.MF., F.C and A.P.B. wrote the manuscript. All authors critically reviewed the manuscript.