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

Abstract

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.

Methods: Whole-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.

Results: The 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.

Conclusion: The 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.

Keywords: Genome; Immune cells; Lung squamous cell carcinoma; PD-L1; TMB.

Fig. 1

Genomic landscape of Chinese LUSC and its correlations with TMB, PD-L1 expression, or immune cells infiltration. a The identified somatic mutations of all cases. b The identified copy number variations of all samples. c–p Association between frequent alterations including TP53 (c), KMT2C (d), NFE2L2 (e), KEAP1 (f), CDKN2A (j), PTEN (k), FBXW7 (l) and PIK3CA (m) mutations, FGFR1 (g), PIK3CA (h), EGFR (i), CCND1 (n) and SOX2 (p) amplification, loss of CDKN2A (o), and TMB. q–r Association between frequent somatic mutations and PD-L1 expression (q), CD8+ TIL expression (r). s–t Association between frequent copy number variations and PD-L1 expression (s), CD8+ TIL expression (t)

Fig. 2

Impact of TMB, PD-L1, CD8+ TIL expression on DFS and OS. a–c Impact of TMB, PD-L1, CD8+ TIL expression on DFS. d–f Impact of TMB plus PD-L1 expression (d), TMB plus CD8+ TIL expression (e) and TMB plus PD-L1 plus CD8+ TIL expression (f) on DFS. g–i Impact of TMB, PD-L1, CD8+ TIL expression on OS. j–l Impact of TMB plus PD-L1 expression (j), TMB plus CD8+ TIL expression (k) and TMB plus PD-L1 plus CD8+ TIL expression (l) on OS

Fig. 3

Classification of tumor immune microenvironment (TIME) based on PD-L1 and CD8+ TIL expression. a The distribution of distinct types of TIME. b Different types of TIME had similar prognosis. c–f Associations between types of TIME and age, sex, smoking history, and TMB. g Different genetic alterations among four types of TIME

Fig. 4

Subgroup analysis according to smoking status. a–f Impact of TMB, PD-L1, CD8+ TIL expression on DFS and OS in never-smoking group. g–l Impact of TMB, PD-L1, CD8+ TIL expression on DFS and OS in ever/current smoking group