The immune contexture and genomic landscape of lung adenomatous premalignancy
- Author(s): Grimes, Brandon Scott
- Advisor(s): Elashoff, Robert M
- et al.
Rationale/Objective: Over the past 30 years, the five-year survival rate for lung cancer has increased by only 5%. A better understanding of genomic alterations and the tumor microenvironment along the spectrum of early disease could lead to identification of targetable neoantigens that may form the basis of future interceptive therapies.
Methods: From 41 lobectomy specimens for early stage lung adenocarcinoma, laser capture microdissection was utilized to obtain multiple areas of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), normal epithelium and the associated ADC for WES. Quantitative IHC and immunofluorescent staining for Granzyme B, PD-1, PDL-1, CD4+, CD8+ and FOXP3 were assessed. Putative neoantigens were identified from ns somatic mutations by prediction of avid binding to patients’ HLA utilizing multiple algorithms in accord with the Immune Epitope Database recommendations.
Results: Non-synonymous (ns) somatic mutations were grouped into the following categories: a) premalignant mutations only observed in premalignant lesions, b) progression-associated mutations (PAMs) located in both premalignant lesions and ADC, and c) malignant-specific mutations only identified in ADC. Neoepitopes derived from PAMs, referred to as progression-associated neoepitopes (PAN), are associated with the highest levels of CD8+ T cell infiltration and PD-L1 expression. Frequent immune-effector cell infiltration and accompanying adaptive immune suppression suggest specific immune antigen recognition of PAN.