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-L1^HighTMB^High 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.