Clinical and immunological implications of frameshift mutations in lung cancer

Abstract Introduction Presently, PD-L1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindel) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindel with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindel in clinical outcomes and immune landscape of NSCLC patients treated with ICIs. Methods We utilized The Cancer Genome Atlas (TCGA) dataset to analyze tumor mutational burden (TMB), neoantigen burden and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindel mutations on disease response rates and survival outcomes. Results Fsindel burden showed positive correlation with TMB and activated CD4/CD8 T-cell infiltration. Presence of fsindel was also associated with significant prolongation of progression free survival (PFS) in patients treated with ICIs (median of 6.2 vs 2.7 months, p = 0.01). In addition, significant differences in the overall response rates (26% vs. 12%, p=0.04) and disease control rates (68% vs. 48%, p=0.02) were observed in patients with fsindel mutations. Conclusion Our findings suggest that fsindel may have a predictive role for ICI response in NSCLC.