Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression, and immune cells infiltration in Chinese lung squamous cell carcinoma

Xianchao Guo,Wei Zhu,Caicun Zhou,Chao Zhao,Likun Hou,Beibei Mao,Zhengwei Dong,Ji He,Xuefei Li,Chunyan Wu,Tao Jiang,Xiaoxia Chen,Chunxia Su,Jinpeng Shi,Henghui Zhang,Shengxiang Ren

doi:10.1186/s13045-019-0762-1

Abstract

IntroductionTo depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates.MethodsWhole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database.ResultsThe median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors.ConclusionThe combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.

Highlights

To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates
The results showed that only KEAP1 mutation was significantly associated with lower CD8+ tumor-infiltrating lymphocyte (TIL) density, and NFE2L2 mutation was associated with marginally higher TMB
Future investigations with a larger number of patients with LUSC are still needed. In summary, this large-scale study found PIK3CA amplification was associated with higher TMB but lower CD8+ T cells density while the common genetic alterations had no impact on PD-L1 expression

Summary

Introduction

To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates. Unlike lung adenocarcinoma (LUAD) with oncogenic driver alterations, therapeutic progress for LUSC is limited and conventional platinum-based chemotherapy remains the standard-of-care for many years [4,5,6]. Immune checkpoint inhibitors targeted programmed cell death 1 (PD-1) and its ligand (PD-L1) has a shift the paradigm in both LUAD and LUSC. Emerging evidence indicated that positive PD-L1 expression and high tumor mutation burden (TMB) could predict the response to anti-PD-1/PD-L1 therapies in NSCLC [12, 13]. Latest reports found gene profiling showed the potent to predict response to immune checkpoint inhibitors [14,15,16]

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Discussion

Conclusion