Neoantigen mining is of great interest for cancer applications. Neoantigens in cancer have been found to be frameshift-mutated non-canonical proteins. We looked at the Non-Canonical Protein Landscape in Non-Small Cell Lung Cancer (NSCLC) and how autoantibodies were produced as an immune response. All alternate Open Reading Frames (altORFs) and ORFs discovered in pseudogenes, noncoding RNAs, and untranslated sections of mRNAs that did not align with known canonical proteins were compiled into a database of cryptoproteins. To determine the presence of cryptoproteins, the proteomic profiles of seventeen Lung Adenocarcinoma (LUAD) cell lines were examined. Plasma Immunoglobulin (Ig)-bound cryptoproteins were analyzed by mass spectrometry to determine the immunogenicity. The specimen collection included 102 control plasmas, pre-diagnostic plasmas from 51 NSCLC cases, and plasmas from 30 newly diagnosed NSCLC cases. 420 cryptoproteins were found after LUAD cell lines were examined. Analyses of plasma Ig-bound proteins discovered 14 cryptoproteins with a fold-change >2 compared to controls and 90 cryptoproteins that were only found in cases. 17 Ig-bound cryptoproteins in pre-diagnostic samples produced an odds ratio of 2. Both pre-diagnostic and recently diagnosed cases had higher levels of eight Ig-bound cryptoproteins when compared to controls. A class of neoantigens known as cryptoproteins causes an autoantibody response in NSCLC.
