Abstract
Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.
Highlights
Thyroid cancer (TC) is the most frequent type of cancer of the endocrine system [1], accounting for approximately 90% of the endocrine malignancies and for 70% of deaths due to endocrine cancers [2]
We have found that the oncolytic adenovirus dl922-947 reduced CXCL8 and CCL2 production by anaplastic thyroid carcinoma (ATC) cell lines. dl922-947 treatment impaired angiogenesis and favored the switch of tumor macrophages toward an M1 phenotype
A low intratumoral CD8+/Foxp3+ ratio was found in human BRAFV600E papillary thyroid carcinoma (PTC), which was associated with an increased expression of the immunosuppressive molecules arginase-1, indoleamine 2,3-dioxygenase (IDO), and programmed death-ligand 1 (PD-L1)
Summary
Thyroid cancer (TC) is the most frequent type of cancer of the endocrine system [1], accounting for approximately 90% of the endocrine malignancies and for 70% of deaths due to endocrine cancers [2]. Differentiated TC (PDTC) and anaplastic thyroid carcinoma (ATC) account for approximately 5–10% of all TCs [7], but the majority of deaths for TC are attributable to this disease [8,9,10]. A mixture of immune cells and proinflammatory mediators has been associated with TC initiation and progression [13]. We discuss recent findings investigating how the cells of the innate and adaptive immune system are involved in TC development and progression. We discuss the rationale and preliminary results of treatment with monoclonal antibodies (mAbs), targeting immune checkpoints in patients with aggressive TCs
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