Tumour-Associated Neutrophils: An H&E-Based Biomarker Predicting Patient Outcomes to Anti-Pd-1 Monotherapy in Lung Adenocarcinoma

Abstract

Purpose: Immune checkpoint blockades are the standard of care for advanced non-small cell lung cancers. Patients with high PD-L1 expression on tumour cells receive anti-PD-1 monotherapy as a first-line treatment. However, more than half of the patients do not respond to the therapy, which demonstrates potential limitations of the current PD-L1 biomarker. Novel biomarkers to identify this treatment-resistant subset of non-small cell lung cancers are needed. Hypothesis: We hypothesize that assessing tumour-associated neutrophil (TAN) in the pre-treatment tumour immune microenvironment will improve prediction of patient clinical outcomes to anti-PD-1 therapy in non-small cell lung cancer. Aim 1: Determine if TAN is a biomarker that associates with response and/or survival in patients with PD-L1high lung adenocarcinomas receiving anti-PD-1 monotherapy. Aim 2: In the PD-L1high cohort, characterize TAN prevalence and survival associations in relation to patient demographics and emerging biomarkers in non-small cell lung cancer. Aim 3: In patients with PD-L1low lung adenocarcinomas receiving combination therapy, evaluate prevalence and clinical outcome associations with TAN. Methodology: Archival diagnostic lung adenocarcinoma specimens assessed for PD-L1 expression were collected. Patients with PD-L1high lung adenocarcinomas were prospectively allocated into discovery (n=27) and validation (n=28) cohorts. A cohort of PD-L1low patients (n=34) was also established. Routine clinical H&E slides were visually assessed for TAN. Results: TAN(+) cases were associated with significantly poor overall survival in both discovery and validation PD-L1high cohorts (p=0.0469 and p=0.0246, respectively). In relation to clinicopathological features, TAN(+) lung adenocarcinomas was independently associated with poor overall survival. The same significant associations were not observed in the PD-L1low cohort.