MA15.10 Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma

Abstract

Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade remains elusive. This study was sought to identify the potential biomarkers that predicted response to PD-1 blockade immunotherapy in lung adenocarcinoma. We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from cohorts of both lung adenocarcinoma public database including The Cancer Genome Atlas (TCGA), GEO repository (GSE72094) and Broad dataset, and clinical immunotherapeutic patients in our center. Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. We observed distinct function of TP53 and KRAS mutation in regulating immune tumor microenvironment (TME). It is TP53 mutation but not KRAS mutation in lung adenocarcinoma that significantly increased expression of immune checkpoints, facilitated CD8+T cell infiltration and activated T-effector and interferon-γ (IFN-γ) signature. Interestingly, TP53 and KRAS co-mutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. More importantly, TP53 or KRAS mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell cycle regulating, DNA replication and damage repair. Finally, clinical immunotherapeutic data were further confirmed that TP53 or KRAS mutation lung adenocarcinoma patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 blockade immunotherapy. This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.