肺腺癌细胞分泌IL1F5拮抗IL36γ负调控CD8+TIL诱导肿瘤免疫逃逸的机制研究

Cytokine-induced immune escape in tumor immune microenvironment is an important cause of poor prognosis in patients with lung adenocarcinoma. We have found that elevated IL1F5 expression is closely related to pathological stage and worse prognosis in lung adenocarcinoma. The carcinogenic effect of IL1F5 depends on the exist of immune cells, which can counteract the proliferation and activation of CD8+TIL induced by IL36γ. Increased IL1F5/IL36γ ratio was positively correlated with the progression of the disease. Based on these findings, we hypothesis that " IL1F5 secreted by lung adenocarcinoma cells can competitively binds to the receptor of IL36γ on the surface of CD8+TIL, induces immune escape and promotes tumor progression". In this study, an expression / silencing strategy was proposed to demonstrate that IL1F5 could induce immune escape in vitro and in vivo, and to evaluate the effect of IL1F5/IL36γ relative concentration on CD8+TIL mediated immune response. Co-IP and GST-pull down were used to elucidate the direct evidence of competitive binding to receptor IL-1Rrp2, and tissue multispectral technique was used to verify the relationship between the expression of IL1F5 and IL36γ and TIL. The detail mechanism of immune escape induced by IL1F5 in lung adenocarcinoma has not been reported, which can provide a new target for immunotherapy of lung adenocarcinoma.

TIME中细胞因子诱导的免疫逃逸是LUAD患者预后差的重要原因。前期研究发现，LUAD组织中IL1F5表达上调与病理分期和预后密切相关，其促癌作用由免疫细胞介导，并可抵消IL36γ促进CD8+TIL增殖活化的作用，且IL1F5/IL36γ比值升高与疾病进展呈正相关。据此提出“LUAD细胞分泌IL1F5与CD8+TIL表面IL36γ的受体竞争性结合，诱导免疫逃逸，促进肿瘤进展”的假说。本项目拟利用过表达/沉默策略，体内外论证LUAD细胞分泌IL1F5诱导免疫逃逸；评估IL1F5/IL36γ比值对CD8+TIL介导的免疫应答的影响，利用co-IP、GST-pull down阐明二者与受体IL-1Rrp2竞争性结合的直接证据；采用组织多光谱技术验证临床样本中IL1F5和IL36γ的表达与TILs浸润的关系。IL1F5诱发LUAD免疫逃逸机制的研究，将为肺腺癌免疫治疗提供新靶点。

肿瘤免疫微环境中细胞因子诱导的免疫逃逸是肺腺癌患者预后差的重要原因。前期研究发现，肺腺癌组织中IL1F5表达上调与病理分期和预后密切相关，其促癌作用由免疫细胞介导，并可抵消IL36γ 促进CD8+TIL增殖活化的作用，且IL1F5/IL36γ比值升高与疾病进展呈正相关。据此提出“肺腺癌细胞分泌IL1F5与CD8+TIL表面IL36γ的受体竞争性结合，诱导免疫逃逸，促进肿瘤进展”的 假说。本项目拟利用过表达/沉默策略，体内外论证肺腺癌细胞分泌IL1F5诱导免疫逃逸；评估IL 1F5/IL36γ比值对CD8+TIL介导的免疫应答的影响，利用co-IP、GST-pull down阐明二者与受体IL-1Rrp2竞争性结合的直接证据；采用组织多光谱技术验证临床样本中IL1F5和IL36γ的表达与肿瘤浸润性淋巴细胞的关系。IL1F5诱发肺腺癌免疫逃逸机制的研究，将为肺腺癌免疫治疗提供新靶点。