Abstract 1098: Mediators of early immune response in bronchial premalignant lesions

Abstract

Abstract Introduction: Bronchial premalignant lesions (PMLs), precursors to lung squamous cell carcinoma, represent a relevant system for studying early tumor development. Some PMLs will progress through increasing grades of dysplasia to become squamous cell carcinoma, while others will regress back to normal airway without intervention. Previous work has identified molecular subtypes of PMLs and identified immune alterations associated with lesion progression/persistence and regression. Here, we used gene expression profiling to identify genes that may be responsible for immune suppression or activation in PMLs. Methods: We collected endobronchial biopsies (n=295) longitudinally from 50 high-risk smokers in approximately one-year intervals at Roswell Park Comprehensive Cancer Center. Two biopsies were collected from each lesion, one for standard pathological assessment and one for RNA sequencing. We derived eight immune-related gene expression phenotypes based on immune-oncologic gene coexpression signatures taken from literature sources. Mediation analysis was used to identify genes that may be upstream modulators or downstream effectors of the association between immune phenotypes and lesion progression/persistence. Gene-Set Enrichment Analysis (GSEA) and Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) were used to identify specific signaling and transcription pathways that these mediators were acting through. Results: Predicted immune phenotypes related to B cell activation, interferon signaling, and antigen presentation were significantly associated with lesion progression/persistence within the Proliferative molecular subtype (FDR ≤ 0.01). Via mediation analysis, we identified 15 genes as candidate immune regulators or downstream immune effectors essential for activation/suppression of the immune response in PMLs. One of these genes, GSTP1, is up-regulated in progressing lesions and negatively correlated with several immune activation pathways, thus representing a possible mechanism for immune suppression in these lesions. Further in silico analysis suggests that GSTP1 acts as a repressor of STAT3 signaling and NF-κB pathways, and in vitro experiments are underway to determine if suppression of GSTP1 is sufficient to induce expression of these immune pathways. Conclusion: Therapies are needed to intercept lung cancer development and these results suggest a targetable pathway to activate the immune system to stimulate PML regression. Citation Format: Carter Merenstein, Julia Breda, Sarah Mazzilli, Eric Burks, Christopher Stevenson, Mary Reid, Avrum Spira, Marc Lenburg, Jennifer Beane. Mediators of early immune response in bronchial premalignant lesions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1098.