Objectives : Deciphering how IL4I1 promotes pro-tumor properties of melanoma-associated macrophages
Methods : Spectral flow-cytometry, imaging, co-culture, in vivo neutralization, ELISA multiplex
Results :
1. Mφ overexpress IL4I1 during melanoma progression
Recently we established the role of IL-4 induced gene 1 (IL4I1) in tumor escape in mice transgenic for the human RET oncogene. We also showed that this enzyme is mainly expressed by a fraction of macrophages (Mφ) on human primary cutaneous melanoma sections and is associated to a reduced patient survival.
We deeply characterized intra-tumoral Mφ subsets in the RET model, with a particular focus on those positive for IL4I1. Our data show an upregulation of IL4I1 expression by a fraction of IDO1⁺ ARG-1⁺ Mφ in the course of melanoma progression that may participate to disease aggressiveness.
2. IL4I1⁺ Mφ specific contribution in tumor escape
We set-up conditional mice in which IL4I1 is specifically inactivated in Mφ. IL4I1KO^Mφ mice transplanted with B16 melanoma cells exhibited a delay of tumor outgrowth and a reduced proportion of exhausted PD1⁺ TIGIT⁺ TIM-3⁺ T cells within the tumor microenvironment compared to IL4I1WT^Mφ littermates.
3. Mechanism of IL4I1 induction in melanoma
We observed up-regulation of IL4I1 in Mφ cultured in presence of either RET tumor cell lines or tumor derived soluble factors containing IL-12, IL-1β, IL-6 and IL-8. Only recombinant IL-1β, among all tested candidates, was able to induce IL4I1 expression in vitro. In support of a role of IL-1β in melanoma, IL4I1 expression by Mφ was decreased when RET mice were treated with an antibody neutralizing IL-1β.
Conclusion
IL4I1⁺ Mφ infiltrating RET melanoma co-express IDO1 and ARG-1 immunosuppressive enzymes. They promote tumor development through the impairment of tumor-infiltrating T cell functions. Deciphering mechanisms driving IL4I1 in tumor-associated Mφ may help to identify new potential targets for immunotherapy.