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 are not fully understood. 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. We observed that mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of Meanwhile, or -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 or 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 or mutation patients, especially those with co-occurring mutations, showed remarkable clinical benefit to PD-1 inhibitors. This work provides evidence that and mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. .

Implications of the tumor immune microenvironment for staging and therapeutics

“…As with hypermutated, microsatellite-high tumors of the colon, endometrium, and other sites, highly mutated lung cancers with smoking-related, transversion-high signatures appear significantly more likely to overexpress PDL1 and to respond to PD-1 inhibition. 36,91 Mechanistically, smoking-related transversion mutations in non-small-cell lung carcinoma contribute to neoantigen formation with resulting T-cell recruitment. IFN- γ release from tumor-infiltrating T cells may trigger adaptive upregulation of tumor PD-L1 and engagement with PD-1 expressing T cells, preventing immune attack.…”

“…Some studies have failed to identify a correlation between tumor genotype and immunoprofile, 92 while others have suggested that KRAS/TP53 mutation status predicts for tumor adaptive immune resistance that may be amenable to PD-1 pathway blockade. 91 STK11 loss-of-function mutations, which occur in 10–15% of lung adenocarcinomas, tend to co-occur with KRAS mutations, appear to promote recruitment of neutrophils to the tumor and exclude T-cell infiltrates, 93–95 and thus may confer relative resistance to immune checkpoint blockade. Therefore, it is likely that tumor genetics have an important role in defining the non-small-cell lung carcinoma tumor immune response.…”

Molecular Pathology of Lung Cancer

“…Son yıllarda yapılan pek çok PD-L1 immünhistokimya uzlaşma çalışması da bu karışıklığı çözmeye yönelik adım atmayı hedeflemektedir (54). Tümör hücrelerinde izlenen PD-L1 immünhistokimyasal pozitifliğinin, sigara kullanımı, artmış somatik mutasyonlar ve yeni antijen ekspresyonlarıyla karakterize TP53 ve KRAS gibi mutasyonlarla birlikteliği, yüksek mutasyon oranına sahip tümörlerde immünoterapinin daha etkili olacağı düşüncesini desteklemektedir (55,56).…”

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

“…Thus, the purpose of recent studies has been the identification of immune-editing of T cells during tumor development, as well as the determination of their potential applications for tumor-specific immunotherapy 164 . …”

“…In one study, the efficacy of immune checkpoint inhibitors among NSCLCL patients was found to correlate with the KRAS mutation as a molecular smoking signature 165 . Other evidence indicates that the co-mutation of TP53 and KRAS in lung adenocarcinoma can be exploited as a potential predictive marker for effective immune checkpoint blockade immunotherapy 164 . Clinical trials have also been initiated for the KRAS -G12D-specific cancer vaccine TG01/ GM-CSF either alone or combined with gemcitabine.…”