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

TLDR

The study aims to determine whether TP53 and KRAS mutation status can predict response to PD‑1/PD‑L1 blockade in lung adenocarcinoma. Using integrated genomic, transcriptomic, proteomic, and clinical data, the authors performed GSEA and molecular analyses that revealed TP53 or KRAS mutations alter cell‑cycle, DNA replication, and repair pathways and modulate immune signatures. TP53 mutation alone upregulated immune checkpoints and IFN‑γ signatures, while TP53/KRAS co‑mutations exhibited the highest PD‑L1+/CD8A+ expression and, together with higher mutation burden, were associated with markedly improved clinical benefit to PD‑1 inhibitors. Clin Cancer Res 23(12):3012‑3024; ©2016 AACR.

Abstract

Purpose: 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.Experimental Design: 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.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ Meanwhile, 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, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.