DataSheet_2_MMP11 is associated with the immune response and immune microenvironment in EGFR-mutant lung adenocarcinoma.xlsx

BackgroundHigh expression of matrix metalloproteinase-11 (MMP11) is associated with various tumors and immune microenvironments. Conversely, poor response to immunotherapy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients is closely related to the characteristics of immune microenvironment.
MethodsThe Cancer Genome Atlas (TCGA)-LUAD database and our gathered clinical LUAD samples were used to examine the relationship between MMP11 expression and EGFR mutation. Then the correlation between MMP11 and immune response and the difference of immune cell infiltration in different groups were analyzed. Compared the differences in the immune microenvironment between the MMP11-positive and MMP11-negative expression groups using immunohistochemistry (IHC) and multiplex immunohistochemistry.
ResultsThe expression of MMP11 in samples with exon 19 deletions, exon 21 L858R or de novo exon 20 T790M mutations was higher than wild type, but there was no difference between the samples with uncommon mutation and the wild-type. The high MMP11 expression group had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. Pathways associated with enrichment in the extracellular matrix (ECM) were the main biological functions of differential genes between the high and low MMP11 groups. The IHC score of MMP11 in the EGFR-mutant group was higher than in the EGFR-wild group. In TCGA-LUAD, the high MMP11 group had a lower proportion of T cell CD8+ and NK cells activated. In the clinical samples, the infiltration levels of T cell CD8+ and NK cells in the tumor parenchyma of EGFR-mutant LUAD was lower in the MMP11-positive than in the MMP11-negative group. The expression levels of tumor cell PD-L1 were higher in the MMP11-positive expression group than in the MMP11-negative expression group, and the proportion of PD1+CD8+ T cells infiltrated was reduced in the MMP11-positive group compared to the MMP11-negative group.
ConclusionsHigh expression of MMP11 was associated with EGFR mutations. Patients with EGFR-mutant LUAD with high expression of MMP11 responded poorly to immunotherapy, and the percentage of T cell CD8+ and NK cells in immune cell infiltration was lower in MMP11. Consequently, MMP11 is related to the immunological microenvironment of EGFR-mutant lung adenocarcinoma, which may be a predictor of possible immunotherapeutic response.

背景 基质金属蛋白酶-11（matrix metalloproteinase-11, MMP11）的高表达与多种肿瘤及免疫微环境密切相关。反之，表皮生长因子受体（epidermal growth factor receptor, EGFR）突变型肺腺癌（lung adenocarcinoma, LUAD）患者对免疫治疗应答不佳的现象，与免疫微环境特征紧密相关。
方法 本研究采用癌症基因组图谱（The Cancer Genome Atlas, TCGA）-LUAD数据库及本课题组收集的临床LUAD样本，分析MMP11表达与EGFR突变之间的关联；随后探究MMP11与免疫应答的相关性，以及不同分组间免疫细胞浸润的差异。采用免疫组织化学（immunohistochemistry, IHC）及多重免疫组织化学技术，对比MMP11阳性表达组与阴性表达组的免疫微环境差异。
结果 携带19号外显子缺失、21号外显子L858R或新发20号外显子T790M突变的样本中，MMP11表达水平高于野生型样本；但携带罕见突变的样本与野生型样本的MMP11表达无显著差异。MMP11高表达组的肿瘤免疫功能异常与排斥（Tumor Immune Dysfunction and Exclusion, TIDE）评分更高。MMP11高低表达组间差异基因的主要生物学功能富集于细胞外基质（extracellular matrix, ECM）相关通路。EGFR突变组的MMP11免疫组织化学评分高于EGFR野生型组。在TCGA-LUAD队列中，MMP11高表达组的活化CD8阳性T细胞及自然杀伤细胞占比更低。在临床样本中，EGFR突变型LUAD患者的肿瘤实质内，MMP11阳性组的CD8阳性T细胞与自然杀伤细胞浸润水平低于MMP11阴性组。MMP11阳性表达组的肿瘤细胞程序性死亡配体1（programmed death-ligand 1, PD-L1）表达水平高于阴性组，且与阴性组相比，阳性组中浸润的PD-1阳性CD8阳性T细胞占比降低。
结论 MMP11高表达与EGFR突变密切相关。携带EGFR突变且MMP11高表达的LUAD患者对免疫治疗应答不佳，其免疫细胞浸润中CD8阳性T细胞与自然杀伤细胞的占比更低。综上，MMP11与EGFR突变型LUAD的免疫微环境相关，或可作为免疫治疗应答潜力的预测标志物。