In silico evaluation of the immunogenic profile of lung cancers with SMARCA4 genetic alterations

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.