In-depth MS-based analysis of NSCLC tumors defined six proteome subtypes, resulting in significant advancement of clinically valuable information. Examples include: 1) OS was best in subtype 1 and worst in subtype 5; 2) signaling aberration and overactivation of mTOR signaling were features of subtype 4 (potentially contributing to both immune evasion and cancer growth); 3) hot immune subtypes differed with respect to phenotypes of infiltrating cells; 4) B cells markers and PD-L1 were expressed dichotomously; and 5) cold immune subtypes expressed very high levels of non-canonical neoantigens (a most unexpected finding).
Contributed by Margot O’Toole
ABSTRACT: Despite major advancements in lung cancer treatment, long-term survival is still rare and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune-evasion mechanisms. Here we performed in-depth mass-spectrometry-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints. Unexpectedly, high neoantigen burden was linked to global hypomethylation and complex neoantigens mapped to genomic regions, such as endogenous retroviral elements and introns, in immune-cold subtypes. Further, we linked immune evasion with LAG-3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition mass-spectrometry-based NSCLC subtype classification method, validate it in an independent cohort of 208 NSCLC cases and demonstrate its clinical utility by analyzing an additional cohort of 84 late-stage NSCLC biopsy samples.
Author Info: (1) Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden. (2) Division of Oncology, Department of Clinical Sciences, Lund
and CREATE Health Strate
Author Info: (1) Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden. (2) Division of Oncology, Department of Clinical Sciences, Lund
and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. (3) Department of Pathology, Laboratory Medicine
Region Skåne, Lund, Sweden. (4) Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. (5) Section of Oncology, Drammen
Hospital, Vestre Viken Health Trust, Drammen, Norway. (6) Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo,
Norway. (7) University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen’s Medical Research Institute, Edinburgh
bioQuarter, Edinburgh, UK. (8) MRC Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
(9) Genomic Medicine Center, Karolinska University Hospital, Stockholm, Sweden. (10) Clinical Genomics Facility, Department of Microbiology, Tumour and
Cell Biology, Karolinska Institutet, Stockholm, Sweden. (11) Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.
(12) Department of Oncology, Oslo University Hospital, Oslo, Norway. (13) Faculty of Medicine, University of Oslo, Oslo, Norway. (14) These authors contributed equally: Janne Lehtiö, Lukas M. Orre.
