Characterizing Response to Neoadjuvant Anti-PD-1 Therapy in Non-Small Cell Lung Carcinoma
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Authors
Cohen, Emily
Date
Type
thesis
Language
eng
Keyword
Immunotherapy , anti-PD-1 , Multiplex immunofluorescence , Cancer immunology
Alternative Title
Abstract
Purpose: Approximately 40% of non-small cell lung carcinoma (NSCLC) patients are resistant to anti-PD-1 treatment. While neoadjuvant application has improved efficacy, current predictive biomarkers for therapeutic response demonstrate limited efficacy in early-stage disease. Developing predictive biomarkers for neoadjuvant anti-PD-1 treatment and gaining a better understanding of mechanisms of resistance is crucial to ensure patient quality of life.
Hypothesis and Aims: We hypothesize that a high degree of PD-L1+ immune cell infiltration within pre-treatment specimens will be associated with response to neoadjuvant anti-PD-1, while low immune infiltration and separate immunosuppressive mechanisms in post-treatment specimens will associate with non-response. Aim 1: Assess pre-treatment tumour microenvironment (TME) for evidence of pre-existing PD-1 and PD-L1 expression and observe relationship with response. Aim 2: Determine effect of therapy on TME through comparison of paired pre- and post-treatment specimens. Aim 3: Characterize features of response and resistance to treatment through examination of post-treatment TME.
Methodology: Pre- and post-treatment samples from 34 NSCLC patients were stained with a six-marker multiplex immunofluorescence assay to characterize cell subsets impacted by the PD-1/PD-L1 axis. Cell density was calculated following digital image analysis classifying each cell as positive or negative for markers within the multiplex immunofluorescence panel. Response was designated as ≥90% tumour regression following treatment and surgical resection. Single-cell RNA sequencing was performed on select subsets to explore cell function.
Results: Intratumoural density of CD8+ T cells within pre-treatment specimens was significantly associated with anti-PD-1 response, with the CD8+FoxP3+ population showing the strongest predictive capacity (p=0.01). These CD8+FoxP3+ cells demonstrate distinct transcriptional profiles from regulatory T cells, with their immediate immune milieu serving as hallmarks of an effective anti-tumour immune response. Patterns among immune cell density over neoadjuvant anti-PD-1 treatment were inconclusive.
Significance: CD8+FoxP3+ T cells present a potential predictive biomarker for neoadjuvant anti-PD-1 therapy. Further study will elucidate the exact function of these cells within the tumour microenvironment, as well as identify mechanisms of resistance that could be targeted to improve treatment efficacy.
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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.