黑色素瘤NOS1亚硝化修饰IRF7促进肿瘤微环境中免疫逃逸的作用和机制

一氧化氮（NO）是免疫调控和效应分子。肿瘤微环境中，NO促进免疫抑制细胞富集，抑制T细胞增殖、趋化和抗原识别等功能。我们前期研究发现，黑色素瘤表达一氧化氮合酶1（NOS1），降低T细胞抗肿瘤疗效。我们近期研究显示，黑色素瘤NOS1亚硝化修饰干扰素调控因子7（IRF7），下调I型干扰素转录，抑制肿瘤组织中巨噬细胞聚集和T细胞激活。据此提出科学假说：黑色素瘤NOS1亚硝化修饰IRF7，阻断肿瘤细胞I型干扰素转录和免疫应答正反馈调控，下调肿瘤细胞免疫应答和组织巨噬细胞成熟激活，启动免疫抑制微环境形成。本课题将研究：1）黑色素瘤NOS1 亚硝化修饰IRF7，抑制免疫应答正反馈调控和I型干扰素转录的机制；2）明确肿瘤IRF7亚硝化促进巨噬细胞M1向M2极化，导致肿瘤免疫逃逸的作用；3）分析NOS1及亚硝化蛋白与临床肿瘤免疫逃逸的相关性。为黑色素瘤治疗和诊断提供亚硝化修饰的靶点和标志物。

Nitric oxide (NO) is an immune regulatory and effector molecule. In the tumor microenvironment, NO promotes the enrichment of immunosuppressive cells and inhibits T cell proliferation, chemotactic and antigen recognition. Our previous study found that melanoma expressed nitric oxide synthase 1 (NOS1), inhibited the signal transduction of type I interferon, and reduced the efficacy of anti-tumor therapy of T cells. Our recent study showed that melanoma NOS1 nitrosation-modified interferon regulator factor 7 (IRF7) inhibits macrophage aggregation and T cell activation in tumor tissues. Therefore, we hypothesis that : melanoma NOS1 induced nitrosation modification of IRF7 could inhibit the positive feedback in the immune response of tumor cells，which promotes the transform of macrophages into immunosuppressive cells and initiates the formation of immunosuppressive microenvironment of tumor. This subject will study: 1) the mechanism of melanoma NOS1 nitrifying IRF7 to inhibit positive feedback of tumor cell immune response and type I interferon paracrine; 2) to clarify the role of tumor IRF7 nitrosation in promoting the polarization of macrophages from M1 to M2 and leading to tumor immune escape; 3) to analyze the correlation between NOS1 and/or nitrite proteins and immune escape of clinical tumors. Thus, it provides targets and markers based on NOS1 induced nitrosation modification for the treatment and diagnosis of melanoma.