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Sonia Moretti, Elisa Menicali, Nicole Nucci, Martina Guzzetti, Silvia Morelli and Efisio Puxeddu

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

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Cosimo Durante, Giovanni Tallini, Efisio Puxeddu, Marialuisa Sponziello, Sonia Moretti, Claudia Ligorio, Antonio Cavaliere, Kerry J Rhoden, Antonella Verrienti, Marianna Maranghi, Laura Giacomelli, Diego Russo and Sebastiano Filetti

Objective

Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear.

Design

The aim of our study was to investigate the impact of BRAF V600E on proangiogenic gene expression and microvascular features of PTCs.

Methods

mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFR β or PDGFRB) were measured with real-time PCR in BRAF V600E (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF V600E cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF V600E mutation in thyrocyte lines.

Results

Transcript levels of proangiogenic factors were significantly lower in BRAF V600E PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF V600E mutation was induced (P=0.01) and increased when it was silenced (P=0.01).

Conclusions

Compared with BRAF-wt PTCs, those harboring BRAF V600E exhibit downregulated VEGFA, VEGFR, and PDGFR β expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.