肿瘤细胞治疗研究
英文原题：Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.
我们的蛋白质基因组学分析突出了无 EGFR 和 ALK 改变的 NSLA 的免疫抑制特性，并确定了新的治疗靶点。这些发现可能提供新的治疗策略，从而改善 NSLA 患者的临床结局。
从不吸烟者肺腺癌（NSLA）与吸烟者肺腺癌相比，表现出独特的免疫抑制特征和较低的肿瘤突变负荷。这些特征与免疫检查点抑制剂反应不佳相关。在本研究中，我们旨在阐明无表皮生长因子受体（EGFR）或间变性淋巴瘤激酶（ALK）变异的NSLA的肿瘤免疫微环境，并确定新的治疗靶点。
我们分析了102例NSLA肿瘤样本和16例正常邻近组织的基因组、转录组和蛋白质组数据。通过分析肿瘤浸润免疫细胞，我们根据基因特征将肿瘤分为不同的免疫簇（IC）。
肿瘤被分为三种免疫背景（IC）：热、中间和冷。值得注意的是，只有21例（20.6%）患者表现出热IC，富含细胞毒性T细胞、NK 细胞和B细胞特征，这与改善的无复发生存期相关。冷IC（37.3%）表现出较高的髓源性抑制细胞（MDSC）水平和M2巨噬细胞特征，免疫细胞浸润差，刺激性和趋化性细胞因子和趋化因子表达相对较低。CEACAM1和NECTIN2在中间和冷IC中上调，并与MDSC和M2巨噬细胞浸润相关。这些基因的高表达与较差的生存结局相关。对冷IC中20个与癌症和驱动相关蛋白相关的上调分子进行蛋白-蛋白网络分析，确定XPO 1为关键组分。
BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.
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