Immunogenomic profiling of lung adenocarcinoma reveals high-grade growth patterns are associated with an immunogenic tumor microenvironment

Lung cancer is the leading cause of cancer-related mortality in the United States. Lung adenocarcinoma (LUAD) is the most common subtype and the most epidemiologically and genetically heterogeneous. Pathologists have routinely observed phenotypic heterogeneity among LUAD primary tumors as reflected by distinct patterns of tumor growth. However, despite prior implications on the association of immune-genomic environment and prognosis, this information is not utilized clinically. Herein, applying multiplatform immune-genomic analysis, we investigate two distinct classification systems and demonstrate that high-grade patterns of growth are associated with a distinct immunogenic tumor microenvironment that is predicted with a favorable response to immunotherapy, a finding with growing importance in the era of adjuvant and neoadjuvant immunotherapy. ### Competing Interest Statement AR serves on the Scientific Advisory Board and has received honoraria from Adaptive Biotechnologies. J.V.H 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. ### Funding Statement This study was supported by the NIH CCSG Award (CA016672 (Institutional Tissue Bank (ITB) and Research Histology Core Laboratory (RHCL)) and the Translational Molecular Pathology-Immunoprofiling Moonshot Platform (TMP-IL) at the Department Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center; the Lung Specialized Programs of Research Excellence grant 5 (P50 CA070907). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board (IRB) of M.D. Anderson Cancer Center gave ethical approval of this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors