Investigating the Tumour Microenvironment of Non-Small Cell Lung Carcinoma for Anti-Pd-1 Biomarker Discovery

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Authors
Espinosa, Nicole
Keyword
Pathology , Immunology , Immunotherapy , Cancer
Abstract
Background: Most advanced non-small cell lung cancers (NSCLCs) lack targetable driver mutations and are now treated with PD-1/PD-L1 blockade as standard therapy. Patients with high tumor cell PD-L1 expression (≥50%, PD-L1high) receive anti-PD-1 monotherapy, but the prognosis for advanced NSCLC is poor. Novel biomarkers to identify this treatment-resistant subset of PD-L1high NSCLCs are needed, specifically within the tumour microenvironment. Aim 1: Assess features of the TME in PD-L1high lung adenocarcinomas that may predict resistance to anti-PD-1 Aim 2: Assess the association of tumour-associated neutrophils (TANs) with other clinical and pathologic features Aim 3: Optimize and validate a multiplex panel to characterize features of the TME associated with TANs Methods: Archival diagnostic lung adenocarcinoma specimens collected at Kingston Health Sciences Centre (KHSC) (2010-2021) were assessed for high PD-L1 expression (≥50%), receipt of anti-PD-1 monotherapy, and clinical annotation. Routine clinical H&E/HPS stained slides were visually evaluated for neutrophils by morphology. TAN (+) tumors were defined as those with a minimum of 5 neutrophils per HPF in at least 3 HPFs. Neutrophils within intact tumor epithelium or intra-tumoral stroma were included. Results: TAN(+) specimens were associated with significantly worse overall survival (OS) in the discovery (n=27) and validation (n= 28) cohorts (p=0.0469 and p=0.0246, respectively), By univariate cox regression analysis, TAN(+) was associated with poor OS (HR 3.26: 95% CI 1.47 to 7.23, p=0.004). Other clinicopathological features such as patient age, gender, KRAS status, necrosis, NLR, and smoking history were not significantly associated with OS. Conclusion: Pathologist assessment for TAN on routine H&E/HPS-stained slides is a readily available biomarker that may identify a subset of PD-L1high lung adenocarcinomas with poor outcomes in need of alternative treatment options. Exploration of the import of TAN in other settings (e.g., PD-L1low, squamous histology, and alternative treatment regimens) is warranted.
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