Immune Landscape of Thyroid Cancers: New Insights

Abstract

Immune system plays a key role in cancer prevention as well as in its initiation and progression. During multistep development of tumors, cells must acquire the capability to evade immune destruction. Both in vitro and in vivo studies showed that thyroid tumor cells can avoid immune response by promoting an immunosuppressive microenvironment. The recruitment of immunosuppressive cells such as TAMs (tumor-associated macrophages), TAMCs (tumor-associated mast cells), MDSC (myeloid-derived suppressor cells), TANs (tumor-associated neutrophils) and Tregs (regulatory T cells) and/or the expression of negative immune checkpoints, like PD-L1 (programmed death-ligand 1), CTLA-4 (cytotoxic T-lymphocyte associated protein 4), and/or immunosuppressive enzymes, as IDO1 (indoleamine 2,3-dioxygenase 1), are just some of the mechanisms that thyroid cancer cells exploit to escape immune destruction. Some authors systematically characterized immune cell populations and soluble mediators (chemokines, cytokines, and angiogenic factors) that constitute thyroid cancer microenvironment. Their purpose was to verify immune system involvement in cancer growth and progression, highlighting the differences in immune infiltrate among tumor histotypes. More recently, some authors have provided a more comprehensive view of the relationships between tumor and immune system involved in thyroid carcinogenesis. The Cancer Genome Atlas (TCGA) delivered a large amount of data that allowed to combine information on the inflammatory microenvironment with gene expression data, genetic and clinical-pathological characteristics, and differentiation degree of papillary thyroid carcinoma (PTC). Moreover, using a new sensitive and highly multiplex analysis, the NanoString Technology, it was possible to divide thyroid tumors in two main clusters based on expression of immune-related genes. Starting from these results, the authors performed an immune phenotype analysis that allowed to classify thyroid cancers in hot, cold, or intermediate depending on immune infiltration patterns of the tumor microenvironment. The aim of this review is to provide a comprehensive and updated view of the knowledge on immune landscape of thyroid tumors. Understanding interactions between tumor and microenvironment is crucial to effectively direct immunotherapeutic approaches in the treatment of thyroid cancer, particularly for those not responsive to conventional therapies.

Keywords: TCGA (The Cancer Genome Atlas); immune phenotype; immunoscore; immunotherapy; thyroid cancer; tumor microenvironment (TME).

Figure 1

Representation of immune cells, solule mediators, and negative immune checkpoints in tumor microenvironment (TME) of thyroid tumor histotypes based on the studies carried out so far. TME of DTCs is the most frequently studied also because they are the most common thyroid carcinomas. ATCs have been shown to be richly infiltrated by cells and mediators of immune system. The few works on PDTCs display TAMs and TAMCs in their TME (see text for details).: DTC, differentiated thyroid cancer; ATC, anaplastic thyroid cancer; PDTC, poorly differentiated thyroid cancer; NK, natural killer; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TAMC, tumor-associated mast cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; CD4+T, CD4+ T helper cell; MDSC, myeloid-derived suppressor cell; CXCL, C-X-C motif chemokine ligand; CCL, C-C motif chemokine ligand; TGF-β, transforming growth factor-β; IDO1, indoleamine 2,3-dioxygenase 1; ARG, arginase; CTLA-4, cytotoxic T-lymphocyte associated protein 4; TIM3, T cell immunoglobulin and mucin domain 3; LAG3, lymphocyte activation gene 3; PD-L1, programmed cell death ligand 1.

Figure 2

Current thyroid tumor classification based on cancer cell characteristics (A) and potential classification approach based on immune phenotype (B). Classical classification takes into account cell origin, morphology, mutational status, altered molecular pathways, TNM stage, and signature of the tumor. The specific interaction between tumor and immune system determines the tumor immune phenotype. ATC-like tumors, presenting T cell infiltration both in the tumor center and in invasive margin or only in the tumor center, have a hot or altered immunosuppressed phenotype. Conversely, PDTC-like tumors have a cold or an altered immunoexcluded phenotype, with not or poor T cell infiltration only at invasive margin.