Immunogenomic profiling of lung adenocarcinoma reveals poorly differentiated tumors are associated with an immunogenic tumor microenvironment. (October 2022)

• Record Type: Journal Article
• Authors: Akhave, Neal; Zhang, Jiexin; Bayley, Erin; Frank, Meredith; Chiou, Shin-Heng; Behrens, Carmen; Chen, Runzhe; Hu, Xin; Parra, Edwin Roger; Lee, Won-Chul; Swisher, Stephen; Solis, Luisa; Weissferdt, Annikka; Moran, Cesar; Kalhor, Neda; Zhang, Jianhua; Scheet, Paul; Vaporciyan, Ara A.; Sepesi, Boris; Gibbons, Don L.; Heymach, John V.; Lee, Jack J.; Wistuba, Ignacio I.; Andrew Futreal, P.; Zhang, Jianjun; Fujimoto, Junya; Reuben, Alexandre
• Is Part Of: Lung cancer. Volume 172(2022)
• Page Start: 19
• Page End: 28
• Publication Date: 2022-10
• Subjects: Lung adenocarcinoma -- Adenocarcinoma patterns of growth -- Translational pathology -- Immune microenvironment -- Multiplatform profiling -- Predictors of immunotherapy response; NSCLC non-small cell lung cancer -- LUAD lung adenocarcinoma -- LUSC lung squamous cell carcinoma -- PROSPECT Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax -- IASLC International Association for the Study of Lung Cancer -- ATS American Thoracic Society -- ERS European Respiratory Society -- WHO World Health Organization -- IHC immunohistochemistry -- WES whole exome sequencing -- GLIPH Grouping of Lymphocyte Interactions by Paratope Hotspots -- GEP gene expression profiling -- TCR T-cell receptor -- RFS relapse-free survival -- OS overall survival -- TMB tumor mutation burden -- NSEM non-synonymous exonic mutations -- TAL tumor-adjacent uninvolved lung -- GZMB Granzyme B -- TIL Tumor infiltrating lymphocyte -- EBUS endobronchial ultrasound -- AJCC American joint committee on cancer; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2022.08.007
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Poorly differentiated tumors are associated with high tumor mutation burden. Poorly differentiated tumors are infiltrated by activated, cytotoxic T-cells. Poorly differentiated tumors demonstrate increased expression of PD-L1. Poorly differentiated tumors demonstrate increased T-cell clonality. Abstract: Objectives: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy. Methods: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth ( i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including whole exome sequencing, gene expression profiling, immunohistochemistry, CIBERSORT, and T-cell receptor sequencing was performed and groups were compared for differences in genomic drivers, immune cell infiltrate, clonality, and survival. Finally, multivariate analysis was performed adjusting for pathologic stage and smoking status. Results: Poorly differentiated tumors demonstrated a strong association with smoking relative to moderately differentiated or well differentiated tumors. However, unlike in prior reports, poorly differentiated tumors were not associated with a worse survival after curative-intent resection. Genomic analysis revealed that poorly differentiated tumors are associated with high tumor mutation burden but showed no association with oncogenic drivers. Immune analyses revealed that poorly differentiated tumors are associated with increased T-cell clonality, expression of PD-L1, and infiltration by cytotoxic CD8 T-cells, activated CD4 T-cells, and pro-inflammatory (M1) macrophages. Finally, multivariate analysis controlling for stage and smoking status confirmed independence of immune differences between IASLC grade groups. Conclusions: Poorly differentiated tumors, as defined by the updated IASLC grading criteria, are associated with a distinct immunogenic tumor microenvironment that predicts for therapeutic response to immune agents, including checkpoint inhibitors, and should be included in the clinical trial design of immunotherapy studies in early-stage lung adenocarcinoma.