Multi-dimensional immunoproteomics coupled with in vitro recapitulation of oncogenic NRASQ61R identifies diagnostically relevant autoantibody biomarkers in thyroid neoplasia

The Autoantibodies against Tumor-Associated Antigens as Potential Blood-Based Biomarkers in Thyroid Neoplasia: Rationales, Opportunities and Challenges

“…We further elaborated our top-down research to more comprehensively study the TAAs’ repertoire of the well-differentiated follicular cell-derived thyroid tumors using an extended panel of samples both at the screening and validation steps, as well as the improved multi-dimensional proteomic approach allowing simultaneous analysis of the protein expression differences between NRAS Q61R -expressing and mock-transfected thyroid cells and serum autoantibody reactivity against these proteins [ 139 ]. Using this pipeline, we were able to expand the list of the autoantibody response-eliciting TAAs in follicular cell-derived thyroid tumors by four proteins, namely, glycolytic enzymes pyruvate kinase PKM2 [ 27 , 28 , 29 , 30 , 31 , 32 ] (see Section 3.1 ) and phosphoglycerate kinase PGK1, a thin filament-associated protein calponin-3 CNN3, and the tricarboxylic cycle enzyme fumarate hydratase FH.…”

“…Notably, three of them (PKM2, PGK1, and CNN3) demonstrated highly significant differences in the cognate TAA-AAbs’ frequencies between different histological types of tumors, and each of the cognate TAA-AAbs were capable of 100% specific partitioning of TAA-AAbs-positive cases in a particular group of histological phenotypes: overtly malignant (including classical PTC) + borderline tumors (excluding NIFTP) for PKM2-AAbs+ cases; overtly malignant + borderline FPT (including NIFTP) for CNN3-AAbs+ cases; and non-invasive tumors (FTA/HTA + NIFTP) for PGK1-AAbs+ cases with moderate (30-35%) DSn values ( Figure 2 ). Upon limiting the analysis to FPT (i.e., tumors most frequently falling into TBSRTC DC3 and TBSRTC DC4 categories) and using the combined autoantibody score (AAS) calculated for a three-antigen panel, the pre-test risk of malignancy was successfully reclassified in almost half (46%, 19/41) of FPT patients [ 139 ].…”

Progress in Neoantigen Targeted Cancer Immunotherapies

“…Finally, the antigenic protein spots can be identified by MS (Tjalsma et al, 2008). This approach has been used to identify antigens in different tumor types (Dai et al, 2017;Belousov et al, 2019). Serological analysis of recombinant cDNA expression libraries (SEREX), which combines serological analysis with antigen cloning techniques, is a widely used technique to explore tumors' antigen repertoire.…”

Anti-glutathione S-transferase omega 1-1 (GSTO1-1) antibodies are increased during acute and chronic inflammation in humans

“…Some studies documented an important role of GSTO1-1 in modulating pathophysiological processes through the regulation of NF-κB [ 3 ] as well as NLRP3 pathways [ 4 , 5 ], and the activation of survival pathways upon exposure to chemotherapeutic drugs [ 6 ] was also demonstrated. Increased levels of GSTO1-1 and/or its polymorphisms are also associated with inflammatory conditions [ 7–9 ] as well as with cancer progression [ 10 , 11 ], and the involvement of hypoxia-inducible factors (HIFs) [ 12 ], Nrf2-ARE pathway [ 13 ] and the RAS family of proto-oncogenes [ 14 ] has been proposed. Overall, these findings indicate that GSTO1-1 can play a role in modulating innate immune response as well as cancer cell survival.…”

“…Indeed, the frequency of detectable autoantibodies in ESCC subjects was 44.8% as compared with a 6.7% of positivity in normal serum [ 11 ]. On the other hand, in another study on thyroid cancer, the overexpression of GSTO1-1 was not associated with relevant levels of autoantibodies in serum [ 14 ].…”