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.

Lung squamous cell carcinoma (LUSC) is one of the major subtypes of lung cancer. Non-SMC condensin I complex subunit H (NCAPH) is highly regarded as a valuable biomarker in certain malignant tumors. However, the specific roles of NCAPH in LUSC are not well understood. The objective of this work was to determine the effect of NCAPH on the progression of LUSC and to identify the microRNAs (miRNAs) located upstream of NCAPH that regulate its function. MicroRNA and mRNA expression profiles, as well as clinical data of LUSC (Normal: 49, LUSC: 502), were obtained from the TCGA database for the purpose of differential analysis and survival analysis. The expression of NCAPH and miR-1976 in LUSC cell lines was detected using Quantitative reverse transcription PCR (qRT-PCR) and western blot techniques. In this study, the impact of NCAPH on the proliferation of LUSC cells was assessed using CCK-8 and colony formation assay. Additionally, the effects of NCAPH on the migration and invasion of LUSC cells were evaluated using the Transwell assay. Furthermore, the effects of NCAPH on the apoptosis of LUSC cells were evaluated using flow cytometry. The target miRNAs of NCAPH were predicted using bioinformatics, and the targeting link between miR-1976 and NCAPH was confirmed using a dual-luciferase reporter gene experiment. The findings indicated that the expression of NCAPH was notably elevated in LUSC tissues (P < 0.05), while the expression of its upstream miRNA (miR-1976) was notably reduced (P < 0.05). The dual-luciferase test results indicated that miR-1976 functions as an upstream target miRNA of NCAPH. Low expression of NCAPH may inhibit the proliferation (P < 0.05), migration (P < 0.05), invasion (P < 0.05), and promote apoptosis (P < 0.05) in LUSC cells. However, the suppression of miR-1976 may reverse this inhibitory effect by specifically targeting NCAPH. This study showed that NCAPH can serves as a novel potential oncogenic biomarker for LUSC and its regulation is controlled by upstream miR-1976. miR-1976 can directly targets NCAPH to affect the proliferation, migration, invasion, and apoptosis of LUSC cell.