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

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. 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. 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. 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.

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Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexandre Reuben serves on the Scientific Advisory Board and has received honoraria from Adaptive Biotechnologies. John V. Heymach serves on the Scientific Advisory Committees of AstraZeneca, EMD Serono, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Roche, Leads Biolabs, and RefleXion and provides research support to AstraZeneca, Bristol-Myers Squibb, and Spectrum and has received royalties and licensing fees from Spectrum. All other authors declare no potential conflicts of interest.