Lehtiö J, Arslan T, Siavelis I, Pan Y, Socciarelli F, Berkovska O, Umer HM, Mermelekas G, Pirmoradian M, Jönsson M, Brunnström H, Brustugun OT, Purohit KP, Cunningham R, Asl HF, Isaksson S, Arbajian E, Aine M, Karlsson A, Kotevska M, Hansen CG, Haakensen VD, Helland Å, Tamborero D, Johansson HJ, Branca RM, Planck M, Staaf J, Orre LM
Nat Cancer 2 (11) 1224-1242 [2021-11-00; online 2021-11-22]
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 (MS)-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 LAG3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition MS-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.