Conditional IL4I1 Inactivation Triggers Tumor-Associated Macrophage Reprogramming and CD8+ T-cell Reactivation to Control Melanoma Progression

Tumor-associated macrophages (TAM) represent the main immune population infiltrating cancers, and their abundance is generally correlated with a poor prognosis. The acquisition of protumor properties by TAMs involves several mechanisms, including the expression of immunosuppressive enzymes. In this study, we explored the role of the enzyme IL4-induced gene 1 (IL4I1) expressed by TAMs in murine models of melanoma. We found that IL4I1 expression was increased in subsets of TAMs during spontaneous melanoma progression, and this increase could be blocked by TNFα, IL12, and IL1β coneutralization. Macrophage-specific IL4I1 deletion delayed tumor onset and metastatic dissemination. Mechanistically, targeting IL4I1 restored the antitumor functions of TAMs with increased antigen-presenting capacity and restored the proliferative and cytotoxic capacities of CD8+ T cells. Chemical blockade of IL4I1 partially reproduced these results. Overall, we demonstrate the key role of IL4I1 in TAM-mediated immune escape of melanoma. As most human tumors contain TAMs expressing IL4I1, our results may have implications for cancer immunotherapy.