Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.

尽管最近取得了进展，但许多癌症仍然难以用现有的免疫治疗策略治疗。新的证据表明，肿瘤微环境中局部树突状细胞（DC）的耐受性促进了免疫逃避。在这里，我们描述了黑色素瘤通过旁分泌 Wnt5a-β-连环蛋白-过氧化物酶体增殖物激活受体-γ (PPAR-γ) 信号通路建立免疫特权位点的机制，该信号通路通过驱动 DC 中的脂肪酸氧化 (FAO)上调肉碱棕榈酰转移酶-1A (CPT1A) 脂肪酸转运蛋白的表达。这种FAO转变增加了吲哚胺2,3-二加酶-1 (IDO)的原卟啉IX辅基，同时抑制白细胞介素(IL)-6和IL-12细胞因子的表达，最终增强IDO活性和调节性T细胞的生成。我们证明，在转基因黑色素瘤模型中，阻断该通路可增强抗黑色素瘤免疫力，增强抗 PD-1 抗体免疫疗法的活性，并抑制疾病进展。这项工作暗示了肿瘤介导的局部树突状细胞代谢重编程在免疫逃避和免疫治疗抵抗中的作用。