Abstract:

Immunotherapies targeting checkpoints such as the PD1 inhibitory receptor aim to restore immune defenses against cancer cells, and have revolutionized the treatment of metastatic melanoma. Nevertheless, 60% of patients resist to these treatments, and it remains urgent to identify new targets and new markers for immunotherapy resistance. Amino-acid catabolizing enzymes, due to their immunosuppressive properties, could contribute to therapeutic failure and have recently emerged as potential new targets. This thesis focuses on one of them : Interleukin-4 Induced Gene 1 (IL4I1). This phenylalanine oxidase contributes to tumor escape, as directly evidenced by my team, in mice transgenic for the RET oncogene spontaneously developing metastatic melanoma. In human primary melanoma, IL4I1 is mainly expressed by a fraction of macrophages and is associated with poorer patient survival. However, the mechanisms of action of IL4I1 in the tumor context remain largely unexplored. This thesis work focused on deciphering the role of IL4I1-expressing macrophages in tumor escape by characterizing their phenotype and function, and their influence on the microenvironment. The main results, obtained in RET mouse model, initially identified the presence of a subset of macrophages expressing the IL4I1 enzyme accumulating only at metastatic stage of melanoma. IL4I1 induction mechanism in macrophages in the tumor context was also investigated, and led to the identification of TNF-α as the main factor responsible for enzyme over-expression when mice display metastasis. To establish the specific in vivo contribution of IL4I1+ macrophages to tumor development, conditional mice were generated. The macrophage-specific inactivation of IL4I1 reduced tumor growth in the B16 melanoma cell transplanted model and delayed incidence of primary tumor and metastasis in the RET model, associated with better antitumoral CD8+ T cell response. Interestingly, this inactivation not only reduces the expression of pro-tumoral markers expressed by macrophages themselves, but also reprograms them toward an anti-tumoral profile. These results reveal the key role of IL4I1+ tumor-associated macrophages in melanoma aggressiveness through alteration of anti-tumoral functions of macrophages and CD8+ T cells. As IL4I1 is expressed by macrophages in most of human solid tumors, this study paves the way for targeting specific macrophage subsets to improve anti-cancer immunotherapies.