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

Abstract

The Autoantibodies targeting Tumor-Associated Antigens (TAA-AAbs) emerge as a result of a variety of tumor-related immunogenic stimuli and may be regarded as the eyewitnesses to the anti-tumor immune response. TAA-AAbs may be readily detected in peripheral blood to unveil the presence of a particular TAA-expressing tumor, and a fair number of TAAs eliciting the tumor-associated autoantibody response have been identified. The potential of TAA-AAbs as tumor biomarkers has been extensively studied in many human malignancies with a major influence on public health; however, tumors of the endocrine system, and, in particular, the well-differentiated follicular cell-derived thyroid neoplasms, remain understudied in this context. This review provides a detailed perspective on and legitimate rationales for the potential use of TAA-AAbs in thyroid neoplasia, with particular reference to the already established diagnostic implications of the TAA-AAbs in human cancer, to the windows for improvement and diagnostic niches in the current workup strategies in nodular thyroid disease and differentiated thyroid cancer that TAA-AAbs may successfully occupy, as well as to the proof-of-concept studies demonstrating the usefulness of TAA-AAbs in thyroid oncology, particularly for the pre-surgical discrimination between tumors of different malignant potential in the context of the indeterminate results of the fine-needle aspiration cytology.

Keywords: anti-tumor immunity; autoantibody; biomarker; diagnostics; follicular-patterned thyroid tumor; indeterminate cytology; thyroid cancer; thyroid neoplasm; thyroid nodule; tumor-associated antigen.

Figure 1

A simplified workflow of the management of patients with NTD and DTC [2,3,5,6,7,8,9] (see Section 4.1 for details) along with potential windows for improvement and diagnostic niches (DNs) that various types of biomarkers, including TAA-AAbs, may potentially occupy (arrowheads, see Section 4.2 for details). The type and strength of evidence suggesting the use of TAA-AAbs in particular groups of patients and clinical contexts are represented by the number and color of arrowheads as deciphered in the figure legend (bottom panel). The text boxes representing diagnostic and treatment procedures are colored in light orange. DN—Diagnostic Niche; FNA—Fine-Needle Aspiration; MT—Molecular Test; RAI—Radioactive Iodine; TAA-AAbs—Autoantibodies against Tumor-Associated Antigens; TBSRTC DC—Diagnostic Category (DC) according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC); TI-RADS—Thyroid Imaging Reporting & Data System; TSH—Thyroid-Stimulating Hormone.

Figure 2

Summary of thyroid neoplasia-associated TAAs reported in the literature. Only those TAAs whose cognate TAA-AAbs demonstrate significant (p < 0.05 according to Fisher’s exact test) differences in frequencies between particular groups of individuals (contoured red for TAA-AAbs-high and green for TAA-AAbs-low groups), including relevant combined groups, are listed. Cells corresponding to groups absent from a particular study and to those that do not demonstrate significant differences in TAA-AAbs’ frequencies when compared with other groups in the study are colored and contoured grey, respectively. ATC—Anaplastic Thyroid Carcinoma; cPTC—Papillary Thyroid Carcinoma, classic/conventional type; FTA—Follicular Thyroid Adenoma; HCA—Hürthle Cell Adenoma; FPT—Follicular-Patterned Tumor; FPT-UMP—FPT of Uncertain Malignant Potential; GS—Gene Symbol; M-FPT—Malignant FPT (including Hürthle cell tumors); MTC—Medullary Thyroid Carcinoma; NIFTP—Non-Invasive Follicular thyroid Tumor with Papillary-like nuclear features; NOS—Not Otherwise Specified; TAA—Tumor-Associated Antigen; TC—Thyroid Cancer; Thyroid NC (non-clonal)—non-neoplastic thyroid diseases.