肿瘤微环境中细胞毒性T细胞（CTLs）功能的抑制是肿瘤发生与进展的重要原因。我们前期研究发现：结直肠癌组织高表达ISG15与患者不良预后和肝转移有关；IFNβ刺激的结直肠癌细胞同时高表达ISG15和B7H4；将鼠源性结肠癌细胞株用IFNβ刺激后植入小鼠，小鼠生存期缩短及肿瘤组织内CTLs浸润减少，CTLs杀伤癌细胞的能力降低。这些结果提示，结直肠癌细胞利用微环境中IFNβ增强ISG15、B7H4的表达，进而抑制肿瘤微环境中CTLs的杀伤效应。本项目将展现INFβ/ISG15/B7H4信号途径的调控作用及对肿瘤微环境浸润CTLs的抑制效应，并在人类结直肠癌组织标本和结直肠癌患者外周血CTLs中进行验证。项目研究旨在阐明结直肠癌及其微环境通过IFNβ/ISG15 /B7H4信号通路的调控，抑制CTLs功能，促进肿瘤进展的新理念，为肿瘤免疫治疗提供潜在的靶向分子。

Cellular immunosuppression of the cytotoxic lymphocytes in the microenvironment is one of the important conditioned states for the survival and progression of cancer. Our previous studies have shown that high expression of ISG15 in the colorectal cancer (CRC) tissues is associated with poor prognosis and liver metastasis of patients with CRC. CRC cells highly expressed ISG15 and B7H4 after exogenous IFNβ stimulation. When murine colonic cells were stimulated with IFNβ and transplanted into mice, the mice died in a short time, and a low level of CTLs infiltrated into the grafted tumors, CTLs showed a decreased capability of cancer cell-killing as well. These data suggested that CRC cells might take advantages of IFNβ in the microenvironment, and up-express ISG15 and B7H4, thereby inhibit the lethal effect of CTLs in the tumor microenvironment. This study demonstrates IFNβ/ISG15/B7H4 modulates cytotoxic lymphocytes in colorectal cancer microenvironment and CTLs immunosuppressive effects in the microenvironment. Finally, the findings should be verified in the human CRC tissues and the CTLs in the peripheral blood of CRC patients. This study is aimed to demonstrate a novel mechanics of colorectal cancer and microenvironment through the signal pathway of IFNβ/ISG15/B7H4 in provoking cellular immunosuppression and strengthen cancer progression. The mechanistic findings may give rise to provide potential molecules for cancer immunotherapy.