Emerging therapeutic options for follicular-derived thyroid cancer in the era of immunotherapy

Abstract

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

Keywords: immunotherapy; mutational landscape; targeted therapy; thyroid cancer; tumor immune microenvironment.

Figure 1

Follicular-derived thyroid cancer evolution. Well-differentiated TC histotypes (PTC, FTC, and OCA) are characterized by driver mutations in BRAF, RAS, RET, and mitochondrial DNA. It is thought that these DTCs, through the accumulation of various mutations, become less differentiated and more aggressive, potentially leading to ATC. Created with BioRender.com.

Figure 2

Signaling pathways and key mutations involved in thyroid cancer tumorigenesis and targeted therapies. Overview of the MAPK (left) and PI3K/AKT (right) pathways which are aberrantly activated in TC. Common mutations resulting in a loss or gain of function are depicted in red and green, respectively. Dashed arrows show targets of multi-kinase inhibitors (RET, PDGFR, and VEGFR) and single kinase inhibitors targeting BRAF, MEK, or mTOR. Created with BioRender.com.

Figure 3

Schematic representation of the tumor microenvironment in thyroid cancer. Thyroid cancer (TC) is characterized by a complex tumor microenvironment (TME) with multiple interactions between tumor cells and various immune and stromal cells. Tumor cells induce activation and differentiation of fibroblasts into myCAFs or iCAFs by releasing multiple factors such as TGFβ, EGF, PDGF, HGF, IGF, etc. In return, myCAFs promote tumor progression and angiogenesis. The iCAF subset attracts and induces suppressive functions of myeloid cells by releasing inflammatory cytokines. ATC tumor cells induce M2 macrophage polarization through TIM3 expression. M2 macrophages and MDSCs play a key role in inhibiting T cell effector function in TC. Immature DCs also suppress the cytolytic functions of T cells and CD56^dimCD16⁺ NK cells in ATC. Tumor cells also recruit neutrophils which act to promote cancer cell proliferation and invasiveness. The TME in ATC is characterized by an expansion of exhausted CD8⁺ T cells expressing PD1, CTLA4, and TIM3 and of an immunosuppressive NK subset (CD56^bright CD16^low). Dashed arrows show immune checkpoint inhibitors targeting PD-1 and CTLA-4. Created with BioRender.