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

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.

• Authors: Kyle G Mitchell, Marcelo V Negrao, Edwin R Parra, Jun Li, Jianhua Zhang, Hitoshi Dejima, Ara A Vaporciyan, Stephen G Swisher, Annikka Weissferdt, Mara B Antonoff, Tina Cascone, Emily Roarty, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Boris Sepesi
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 109 Issue 2 Pg. 358-366 (02 2020) ISSN: 1552-6259 [Electronic] Netherlands
• PMID: 31550464 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• CD274 protein, human

Topics

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