目标:最近,已经报道了癌症中SWI/SNF染色质重塑基因的失活体细胞突变。然而,关于染色质重塑复合物基因突变肿瘤中肿瘤微环境(TME)的免疫学分析的研究很少.在本研究中,我们确定了携带多种哺乳动物SWI/SNF复合物突变的癌症患者,并研究了这些突变癌症的免疫学特征.
方法:选择具有任何类型染色质重塑复合物基因突变的癌症患者,比较染色质重塑复合物基因低表达组和高表达组的临床病理特征。具体来说,在SMARCA4低表达组和高表达组之间使用火山图分析比较了免疫应答相关基因和癌症相关基因的表达水平.
结果:在携带PBRM1、SAMRACA4和ARID2基因突变的癌症中,T细胞标记和成熟B细胞标记基因在肿瘤中上调。具体来说,T细胞效应基因(CD8B,CD40LG),中央记忆标记基因(CD27,CCR7)和成熟B细胞标记基因(CD20,CD38,CD79和IRF4)表达上调,和癌症相关基因,包括MYB,MYC和AURKB基因在SMARCA4低表达组中下调。值得注意的是,基因表达和免疫组织化学(IHC)数据的热图表明,成熟B细胞的三级淋巴结构(TLS)基因签名在SMACA4基因突变的胃癌中上调。
结论:这些结果表明,免疫肿瘤微环境状态,例如成熟的B细胞募集具有TLS基因签名和由癌症信号下调介导的免疫激活,可能有助于将SMARCA4基因突变的肿瘤分类为免疫检查点阻断治疗敏感的靶肿瘤。
OBJECTIVE: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers.
METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis.
RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers.
CONCLUSIONS: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.