RESUMO
Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer. While ATC is rare, its mortality is high. Standard treatments, such as surgery, radiotherapy, and chemotherapy, have demonstrated limited efficacy in managing ATC. However, the advent of immunotherapy has significantly improved the prognosis for patients with ATC. Immunotherapy effectively targets and eliminates tumor cells by using the power of the body's immune cells. The neoantigen is an atypical protein generated by somatic mutation, is exclusively observed in neoplastic cells, and is devoid of central tolerance. Neoantigens exhibit enhanced specificity towards tumor cells and display robust immunogenic properties. Currently, neoantigen therapy is primarily applied in immune checkpoint inhibitors and cellular immunotherapy, encompassing adoptive immunotherapy and tumor vaccines. This study discusses the mechanism, tumor microenvironment, clinical trials, adverse events, limitations and future directions associated with ATC immunotherapy.
RESUMO
BACKGROUND: Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action. MATERIALS AND METHODS: The effects of ribavirin on thyroid cancer was investigated using in vitro cellular assays and in vivo xenograft mouse model. The mechanism of its action on eIF4E-ß-catenin axis was examined using genetic and biochemical approaches. RESULTS: We show that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E phosphorylation and overexpression of its wildtype and phosphor-mimetic form (S209D) but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated that ribavirin suppressed phosphorylation and activities of ß-catenin and its subsequent gene transcriptional expression. ß-Catenin overexpression rescued the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E regulated ß-catenin and that the regulation depended on phosphorylation at S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and ß-catenin were also observed in thyroid tumor. CONCLUSIONS: Our data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/ß-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-ß-catenin in thyroid cancer.
