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

Ehsan Irajizad1,2, Johannes F Fahrmann1, James P Long2

  • 1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

International Journal of Molecular Sciences
|August 26, 2022
PubMed

Insights

Researchers identified novel cancer neoantigens called cryptoproteins in non-small cell lung cancer (NSCLC). These cryptoproteins trigger an autoantibody immune response, offering potential new avenues for cancer detection and therapy.

Area of Science:

  • Oncology
  • Immunology
  • Proteomics
  • Bioinformatics

Background:

  • Non-canonical proteins from mutations are recognized as cancer neoantigens.
  • Understanding novel neoantigens in non-small cell lung cancer (NSCLC) is crucial for therapeutic development.
  • Autoantibodies against tumor-specific antigens can serve as early diagnostic biomarkers.

Purpose of the Study:

  • To investigate the landscape of non-canonical proteins, termed cryptoproteins, in non-small cell lung cancer (NSCLC).
  • To evaluate the immune response, specifically autoantibody induction, against these cryptoproteins.
  • To assess the potential of cryptoproteins as diagnostic biomarkers for NSCLC.

Main Methods:

  • Computational construction of a cryptoprotein database including alternate open reading frames (altORFs) and ORFs from non-canonical genomic regions.
  • Proteomic profiling of seventeen lung adenocarcinoma (LUAD) cell lines to identify cryptoprotein occurrence.
  • Mass spectrometry-based profiling of immunoglobulin (Ig)-bound cryptoproteins in plasma from NSCLC cases (newly diagnosed and pre-diagnostic) and controls.

Main Results:

  • Identification of 420 cryptoproteins in LUAD cell lines.
  • Discovery of 90 cryptoproteins uniquely present in NSCLC cases and 14 with a fold-change >2 compared to controls in plasma Ig-bound analyses.
  • Detection of 17 Ig-bound cryptoproteins with an odds ratio ≥2 in pre-diagnostic samples, with 8 elevated in both pre-diagnostic and newly diagnosed cases.

Conclusions:

  • Cryptoproteins represent a novel class of neoantigens in non-small cell lung cancer.
  • These cryptoproteins elicit a specific autoantibody immune response in NSCLC patients.
  • The identified cryptoproteins hold potential as early diagnostic biomarkers for NSCLC.
Keywords:
NSCLCaltORFsautoantibodiesneoantigensnoncanonical open reading frames

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