Lymphovascular Invasion Is Associated With Mutational Burden and PD-L1 in Resected Lung Cancer

Ann Thorac Surg. 2020 Feb;109(2):358-366. doi: 10.1016/j.athoracsur.2019.08.029. Epub 2019 Sep 21.

Abstract

Background: High tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are leading biomarkers in metastatic non-small cell lung cancer (NSCLC) and predict favorable response to checkpoint inhibitors. We sought to identify clinicopathologic characteristics associated with elevated TMB and PD-L1 expression among patients who underwent resection for NSCLC.

Methods: NSCLC patients undergoing primary resection (2016-2018) were prospectively enrolled in an immunogenomic profiling project. Multiplex immunofluorescence quantified densities (cells/mm2) of CD3+, CD3+CD8+, CD3+CD8+PD-1+, malignant cells (MCs), MCsPD-L1+, CD68+, CD68+PD-L1+, and CD20+ cells. Whole-exome sequencing quantified TMB (mutations/megabase). TMB and MCsPD-L1+ were dichotomized according to the median of each.

Results: A total of 55 patients completed multiplex immunofluorescence and whole-exome sequencing profiling. In this sample, 41.8% (23 of 55) had pathologic stage I disease. Median TMB and MCsPD-L1+ were 3.91 and 0.62 cells/mm2, respectively. TMB was higher among smokers (P = .001) and tumors with lymphovascular invasion (LVI) (P = .051). TMB was positively correlated with densities of MCsPD-L1+ (r = 0.293, P = .030), CD68+PD-L1+ (r = 0.289, P = .033), and CD20+ (r = 0.310, P = .043) cells. The density of MCsPD-L1+ was associated with increased CD3+CD8+ (r = 0.319, P = .018) and CD68+PD-L1+ (r = 0.371, P = .005) cells. Patients with PD-L1HighTMBHigh tumors (30.9%, 17 of 55) had higher intratumoral densities of CD3+, CD3+CD8+, CD68+, CD68+PD-L1+, and CD20+ cells. On multivariable analysis LVI was associated with synchronous elevated TMB and PD-L1 expression (odds ratio 3.53, P = .039).

Conclusions: NSCLC tumors with elevated TMB and PD-L1 expression are associated with LVI and increased intratumoral immune cell infiltration. These findings may potentially improve patient selection for checkpoint inhibitor therapy trials in the adjuvant setting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • B7-H1 Antigen / genetics*
  • Cancer Care Facilities
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / surgery*
  • Cohort Studies
  • Disease-Free Survival
  • Exome Sequencing
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / surgery*
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Mutation / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Pneumonectomy / methods
  • Pneumonectomy / mortality
  • Proportional Hazards Models
  • Prospective Studies
  • Survival Analysis
  • Texas
  • Time Factors
  • Treatment Outcome
  • Tumor Burden

Substances

  • B7-H1 Antigen
  • CD274 protein, human