Potential Predictive Value Of TP53 And KRAS Mutation To PD-1 Blockade Immunotherapy In Lung Adenocarcinoma

BackgroundRecent clinical trials with anti-programmed cell death 1(PD-1)and its ligand PD-1 ligand(PD-L1)therapies have shown unprecedented durable responses in patients with non-small cell lung cancer(NSCLC).Unfortunately,only a minority of the total of treated patients respond to the current immunotherapy.The factors that determine which patients will be drug sensitive or resistant are not fully understood.Therefore,it has become a primary priority to identify the biomarkers that determine the responsiveness to checkpoint blockade,and to develop strategies that could potentially increase the patient response rates.Encouragingly,recent studies had demonstrated that tumor mutational load,DNA mismatch repair(MMR)deficiency,the intensity of CD8+ T cell infiltrates and intratumoral PD-L1 expression have each been proposed as distinct biomarkers of response to anti-PD-1/PD-L1 therapies.Meanwhile,these factors are functionally interrelated and are often found coordinately in individual tumor specimens.This raises the question of whether there exist some other variables simultaneously affect two or more of these above factors so as to provide stronger predictive value for therapeutic outcomes.MethodsWe performed an integrated analysis on the multiple-dimensional data types including genomic,transcriptomic,proteomic data from cohorts of lung adenocarcinoma public(Discovery Set)and internal(Validation Set)database.Analysis of the correlation between clinical immunotherapeutic efficacy and gene mutation based on the public clinical trial(MSKCC)and our center patients(GLCI).Immunohistochemistry and Sanger sequencing was used for biomarker detection.Gene Set Enrichment Analysis(GSEA)was used to determine potentially relevant gene expression signatures between specific subgroups.ResultsWe firstly analyzed the correlation between lung adenocarcinoma common genes(EGFR/KRAS/TP53/STK11)and PD-L1 expression as well as tumor-infiltrating lymphocytes(TILs)in tumor immune microenvironment by use of public database TCGA and GEO.We identified TP53 mutation and TP53/KRAS co-mutation significantly increased immune checkpoints expression,T cell infiltration and activated T-effector and interferon-γ associated gene signature.Specifically,our findings revealed TP53/KRAS co-mutation selectively increased PD-L1 expression and accompanied with a higher proportion of dual positive PD-L1 and CD8A than other mutation groups.Furthermore,we identified TP53 and KRAS mutated tumors showed prominently increased somatic mutation burden and specifically enriched in the transversion-high subset by analysis of Discovery Set(TCGA and Broad)and Validation Set(GLCI).By analysis of gene set enrichment we TP53 and KRAS mutation impaired cell cycle,DNA replication and DNA damage repair related signaling and in consequence produce more mutations.Based on these discoveries in the molecular mechanism,we presumed that patients with these two mutations in lung adenocarcinomas probably had increased sensitivity to PD-1 blockade immunotherapy.Consistent with our preclinical predictions,the clinical analysis on the base of public clinical trial(MSKCC cohort)had confirmed that those with TP53 or KRAS mutation,especially co-occurring TP53/KRAS mutations showed remarkable clinical benefit from Pembrolizumab.When transfer to the real word clinical immunotherapy(GLCI cohort),we similarly observed favorable clinical efficacy of PD-1 inhibitors in those with TP53 and/or KRAS mutation.ConclusionsThe results of this study highlighted an insight into immune regulation driving by some common mutations of lung adenocarcinoma.We had discovered a prominent significance of TP53 and KRAS mutation in boosting PD-L1 expression,facilitating T cell infiltration and augmenting tumor immunogenicity.Furthermore,we established a significant correlation between TP53/KRAS mutation and the sensitivity to PD-1 blockade immunotherapy.These work provided evidence that TP53 and KRAS mutation in lung adenocarcinoma might be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.