Spatial profiling of the microenvironment reveals low intratumoral heterogeneity and STK11-associated immune evasion in therapy-naïve lung adenocarcinomas.

Intratumoral heterogeneity was found to be a significant factor causing resistance to lung cancer therapies, including immune checkpoint blockade. Lesser is known about spatial heterogeneity of the tumor microenvironment (TME) and its association with genetic properties of the tumor, which is of particular interest in the therapy-naïve setting. We performed multi-region sampling (2-4 samples per tumor; total of 55 samples) from a cohort of 19 untreated stage IA-IIIB lung adenocarcinomas (n = 11 KRAS mutant, n = 1 ERBB2 mutant, n = 7 KRAS wildtype). For each sample the expression of 770 immunooncology-related genes was analyzed using the nCounter platform, while the mutational status was determined by hybrid capture-based next-generation sequencing (NGS) using a large panel covering more than 500 genes. Global unsupervised analyses revealed clustering of the samples into two groups corresponding to a 'hot' or 'cold' immunologic tumor contexture based on the abundance of immune cell infiltrates. All analyzed specific immune cell signatures (ICsig) showed a significantly higher intertumoral than intratumoral heterogeneity (p < 0.02), as most of the analyzed cases (14/19) showed a very homogenous spatial immune cell profile. PD-L1 exhibited a significantly higher intertumoral than intratumoral heterogeneity (p = 1.03e-13). We found a specific association with 'cold' TME for STK11 (11/14, p < 0.07), but not KRAS, TP53, LRP1B, MTOR, U2AF1 co-mutations, and validated this finding using The Cancer Genome Atlas (TCGA) data. Early-stage lung adenocarcinomas show considerable intertumoral, but limited intratumoral heterogeneity, which is clinically highly relevant as assessment before neoadjuvant treatment is based on small biopsies. STK11 mutations are specifically associated with a 'cold' TME, which could affect the efficacy of perioperative immunotherapy.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martina Kirchner has received honoraria (speakers bureau) from Veracyte Inc., and received travel support from Veracyte Inc. Hauke Winter declares: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Intuitive Surgical, Astra Zeneca, Roche Pharma. Support for attending meetings and/or travel: Intuitive Surgical. Claus-Peter Heußel declares: Employment or Leadership Position: Head of Diagnostic and Interv Radiology with Nuclear Medicine, Thoraxklinik Heidelberg, Member of the German Center for Lung Research. Stock ownership in medical industry: GSK. Patent: Method and Device For Representing the Microstructure of the Lungs. IPC8 Class: AA61B5055FI, PAN: 20080208038, Inventors: W Schreiber, U Wolf, AW Scholz, CP Heussel. Personal involvements: Consultation or other fees: Schering-Plough, Pfizer, Basilea, Boehringer Ingelheim, Novartis, Roche, Astellas, Gilead, MSD, Lilly, Intermune, Fresenius. Research funding: Siemens, Pfizer, MeVis, Boehringer Ingelheim, German Center for Lung Research. Lecture fees: Gilead, Essex, Schering-Plough, AstraZeneca, Lilly, Roche, MSD, Pfizer, Bracco, MEDA Pharma, Intermune, Chiesi, Siemens, Covidien, Pierre Fabre, Boehringer Ingelheim, Grifols, Novartis, Basilea, Bayer. Comitee membership: Chest working group of the German Roentgen society, National guidelines: bronchial carcinoma, mesothelioma, COPD, screening for bronchial carcinoma, CT and MR imaging of the chest, Pneumonia, Consultant of ECIL-3, ECCMID, EORTC/MSG, Guideline for diagnosis of infections in immunocompromized hosts, Founding member of the working team in infections in immunocompromized hosts of the German society of Hematology/Oncology, Guideline for diagnosis of infections in immunocompromized hosts, Faculty member of European Society of Thoracic Radiology (ESTI), European Respiratory Society (ERS), and member in EIBALL (European Imaging Biomarkers Alliance), Editor of “Medizinische Klinik, Intensivmedizin und Notfallmedizin”, at Springer publishing. Peter Schirmacher declares: Grants: BMS, MSD, Astrazeneca. Payment: BMS. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, AstraZeneca. Solange Peters declares: I have received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom I have received honoraria (all fees to institution): Consultation / Advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. Boardod Director role: Galenica SA. Talk in a company’s organized public event: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Takeda. Receipt of grants/research supports: Principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, Merck Sharp and Dohme, Roche/Genentech. Michael Thomas has received honoraria (speakers bureau, advisory board) from AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Furthermore he has received travel support from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Petros Christopoulos has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Novartis, Roche, Pfizer, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. Jan Budczies has received grants from German Cancer Aid, and personal consulting fees from MSD, outside the submitted work. Albrecht Stenzinger declares: Advisory Board/Speaker’s Bureau: Astra Zeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher. Grants: Bayer, BMS, Chugai, Incyte. Daniel Kazdal reports personal fees from AstraZeneca, Bristol-Myers Squibb, Pfizer, Lilly, Agilent, Takeda, Illumina, and Incyte outside the submitted work. All other authors have no conflict of interests.