A Comprehensive Search of Non-Canonical Proteins in Non-Small Cell Lung Cancer and Their Impact on the Immune Response

Ehsan Irajizad, Johannes F. Fahrmann, James P. Long, Jody Vykoukal, Makoto Kobayashi, Michela Capello, Chuan Yih Yu, Yining Cai, Fu Chung Hsiao, Nikul Patel, Soyoung Park, Qian Peng, Jennifer B. Dennison, Taketo Kato, Mei Chee Tai, Ayumu Taguchi, Humam Kadara, Ignacio I. Wistuba, Hiroyuki Katayama, Kim Anh DoSamir M. Hanash, Edwin J. Ostrin

Research output: Contribution to journalArticlepeer-review


There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess the immunogenicity, immunoglobulin (Ig)-bound cryptoproteins in plasmas were profiled by mass spectrometry. The specimen set consisted of plasmas from 30 newly diagnosed NSCLC cases, pre-diagnostic plasmas from 51 NSCLC cases, and 102 control plasmas. An analysis of LUAD cell lines identified 420 cryptoproteins. Plasma Ig-bound analyses revealed 90 cryptoproteins uniquely found in cases and 14 cryptoproteins that had a fold-change >2 compared to controls. In pre-diagnostic samples, 17 Ig-bound cryptoproteins yielded an odds ratio ≥2. Eight Ig-bound cryptoproteins were elevated in both pre-diagnostic and newly diagnosed cases compared to controls. Cryptoproteins represent a class of neoantigens that induce an autoantibody response in NSCLC.

Original languageEnglish (US)
Article number8933
JournalInternational journal of molecular sciences
Issue number16
StatePublished - Aug 2022


  • altORFs
  • autoantibodies
  • neoantigens
  • noncanonical open reading frames

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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