Potential Predictive Value of <i>TP53</i> and <i>KRAS</i> Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma

Abstract

<b>Purpose:</b> 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 are not fully understood.<b>Experimental Design:</b> We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.<b>Results:</b> We observed that <i>TP53</i> mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the <i>TP53/KRAS</i> comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of <i>PD-L1⁺/CD8A⁺</i> Meanwhile, <i>TP53-</i> or <i>KRAS</i>-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 <i>TP53</i> or <i>KRAS</i> mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that <i>TP53</i> or <i>KRAS</i> mutation patients, especially those with co-occurring <i>TP53/KRAS</i> mutations, showed remarkable clinical benefit to PD-1 inhibitors.<b>Conclusions:</b> This work provides evidence that <i>TP53</i> and <i>KRAS</i> mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. <i>Clin Cancer Res; 23(12); 3012-24. ©2016 AACR</i>.