Investigating the Tumour Microenvironment of Non-Small Cell Lung Carcinoma for Anti-Pd-1 Biomarker Discovery
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Authors
Espinosa, Nicole
Date
Type
thesis
Language
eng
Keyword
Pathology , Immunology , Immunotherapy , Cancer
Alternative Title
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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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.