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.