Nieto-Jiménez Cristina, Garcia-Lorenzo Esther, Diaz-Tejeiro Cristina, Paniagua-Herranz Lucía, Sanvicente Adrián, Doger Bernard, Moreno Irene, Pedregal Manuel, Bartolomé Jorge, Manzano Arancha, Munkácsy Gyöngyi, Győrffy Balázs, Pérez-Segura Pedro, Calvo Emiliano, Moreno Victor, Ocana Alberto
Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC) Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain.
Sci Rep. 2025 May 22;15(1):17832. doi: 10.1038/s41598-025-02494-x.
Genomic alterations in tumor cells can influence immune response, as has been demonstrated in several tumor types. For instance, mutations in certain genes like EGFR or B-RAF are associated with a particular immune phenotype. Non-small cell lung cancer (NSCLC) is one of the most immunogenic tumors, but certain genomic alterations can modulate and influence immune response. In the present work, we explore the transcriptomic landscape and immunologic profile of NSCLC with molecular alterations in SMARCA4. Using the TCGA repository we exploited their analysis with R and other available packages. cBioPortal was used to explore and analyze the mutational profile present in those tumors The prognostic value of identified genes in patients treated with immunotherapy was evaluated using the KMplotter online tool, and for correlations with immune populations TIMER 2.0 was interrogated. In lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) disruptive mutations in SMARCA4 were presented in 8%, and 4% of the cases, respectively. Gene deletions were observed in 1% of the population. The transcriptomic profile in LUAD and LUSC with deletions or disruptive mutations was explored. Interrogating TCGA using a 2.5 gene expression fold change (FC) we observed five genes commonly upregulated, and thirty-one genes commonly decreased when SMARCA4 was mutated or CNV loss was present. Enriched biological functions for downregulated genes included "Antigen processing and presentation, endogenous lipid antigen via MHC class Ib. Expression of CD1A, CD1C, CD1E, CX3CR1, and MYO1G showed a strong positive correlation with dendritic cells (DC) and dendritic cells resting (DCR). The increased expression of gene signatures formed by these transcripts resulted in a better prognosis in a set of patients with different tumors treated with anti-PD1 therapies, including 21 non-small cell lung cancers. We evaluated genomic alterations and transcriptomic patterns of SMARCA4 alterations in NSCLC tumors, identifying a relevant immunologic downregulated gene set linked with antigen presentation that predicts response to anti-PD1 therapies.
肿瘤细胞中的基因组改变可影响免疫反应，这在多种肿瘤类型中已得到证实。例如，某些基因（如EGFR或B-RAF）的突变与特定的免疫表型相关。非小细胞肺癌（NSCLC）是最具免疫原性的肿瘤之一，但某些基因组改变可调节和影响免疫反应。在本研究中，我们探讨了具有SMARCA4分子改变的NSCLC的转录组景观和免疫特征。利用TCGA数据库，我们使用R和其他可用软件包对其进行分析。使用cBioPortal探索和分析这些肿瘤中存在的突变谱。使用在线工具KMplotter评估鉴定出的基因在接受免疫治疗患者中的预后价值，并使用TIMER 2.0研究与免疫群体的相关性。在肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）中，SMARCA4的破坏性突变分别出现在8%和4%的病例中。在1%的人群中观察到基因缺失。探索了具有缺失或破坏性突变的LUAD和LUSC中的转录组谱。使用2.5倍基因表达变化（FC）查询TCGA，我们观察到当SMARCA4发生突变或存在CNV缺失时，有五个基因通常上调，三十一个基因通常下调。下调基因的富集生物学功能包括“抗原加工和呈递，通过MHC Ib类的内源性脂质抗原”。CD1A、CD1C、CD1E、CX3CR1和MYO1G的表达与树突状细胞（DC）和静息树突状细胞（DCR）呈强正相关。这些转录本形成的基因特征的表达增加导致一组接受抗PD1治疗的不同肿瘤患者，包括21例非小细胞肺癌患者的预后更好。我们评估了NSCLC肿瘤中SMARCA4改变的基因组改变和转录组模式，确定了一组与抗原呈递相关的免疫下调基因，该基因可预测对抗PD1治疗的反应。
