TP53 and LRP1B Co-Wild Predicts Improved Survival for Patients with LUSC Receiving Anti-PD-L1 Immunotherapy

SIMPLE SUMMARY: Immune checkpoint inhibitors (ICIs) changed the standard care of patients with lung squamous cell carcinoma (LUSC). It is an urgent need to precisely predict the population’s response to ICIs. The aim of the study was to explore novel biomarkers for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients with LUSC who underwent targeted sequencing were involved, and TP53 and LRP1B were the genes most frequently correlated to tumor mutational burden (TMB). Further analysis demonstrated that TP53/LRP1B co-wild was associated with improved survival of immunotherapy. Compared with those with TP53/LRP1B mutant, patients with TP53/LRP1B co-wild had lower TMB and chromosome instability, while stronger cytotoxic immune cell infiltrations, which might be the reason for the better clinical outcomes of immunotherapy. These results indicated that TP53/LRP1B co-wild might be regarded as a potential biomarker for guiding anti-PD-L1 immunotherapy in LUSC. ABSTRACT: Immunotherapy brought long-term benefits for partial patients with lung squamous cell carcinoma (LUSC). The predictor of anti-PD-L1 therapy was controversial and limited in LUSC. We aimed to explore novel biomarker for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients (Geneplus cohort) with LUSC underwent targeted sequencing and were involved to explore the genomic profiling. TP53 and LRP1B were the most frequently recurrent genes and correlated to higher tumor mutational burden (TMB). We observed that LUSC patients with TP53 and LRP1B co-wild (co-wild type) were associated with better survival of anti-PD-L1 therapy compared with TP53 mutant or LRP1B mutant (mutant type) in POPAR/OAK cohort. Copy-number variation (CNV) and whole genome doubling (WGD) data from TCGA LUSC cohort were obtained to assess the CNV events. There were fewer CNV alterations and lower chromosome instability in patients with TP53/LRP1B co-wild compared with those with TP53/LRP1B mutant. RNA expression data from the TCGA LUSC cohort were collected to explore the differences in RNA expression and tumor immune microenvironment (TIME) between mutant and co-wild groups. The TP53/LRP1B co-wild type had a significantly increased proportion of multiple tumor-infiltrating lymphocytes (TILs), including activated CD8 T cell, activated dendritic cell (DC), and effector memory CD8 T cell. Immune-related gene sets including checkpoint, chemokine, immunostimulatory, MHC and receptors were enriched in the co-wild type. In conclusion, TP53/LRP1B co-wild LUSC conferred an elevated response rate in anti-PD-L1 therapy and improved survival, which was associated with a chromosome-stable phenotype and an activated immune microenvironment.