852 Potential of immunotherapy for BRAF-Mutated papillary thyroid cancer: insights from immune profiling and BRAF inhibition correlations

<h3>Background</h3> Immune checkpoint inhibitors (ICIs) have become an effective treatment for advanced cancers, but their role in treating papillary thyroid cancer (PTC) remains uncertain. Although CD274 is present in thyroid cancers, trials with CD274 inhibitors have shown limited success, with an overall response rate (ORR) of just 3.8%. These results suggest that factors beyond CD274, including other genes or signaling pathways, may contribute to the poor response to immunotherapy. We aimed to investigate the impact of BRAF mutations and their downstream signaling on the expression of immune suppressive markers in PTC tissues. Additionally, we explored the potential benefits of combining BRAF inhibitors with immunotherapy. <h3>Methods</h3> This retrospective, single-institution cohort study investigates the potential of immunotherapy for BRAF-mutated papillary thyroid cancer (PTC) by analyzing the immune profile of patient samples from the City of Hope and comparing them to the thyroid dataset in the TCGA database. Patients diagnosed with thyroid carcinoma with initial papillary histology and with pathologic slides available for review were included in the study. RNA was extracted from tumor tissues and analyzed using NanoString to assess immune gene expression profiles. Immunohistochemistry (IHC) was conducted to determine the expression of immune suppressive genes and lymphocytic infiltration. Multiplex IHC staining for TTF, CD4, CD8, and CD20 was performed using the Ventana Discovery Ultra automated IHC stainer. The stained tissues were visualized, counterstained, and scanned for analysis. Thyroid cancer cell lines (MDA-T32, MDA-T68, MDA-T85, and MDA-T120) were used to explore the correlation between BRAF inhibition and CD274 expression. <h3>Results</h3> The analysis revealed that PTC cases with BRAF mutations exhibit higher expression of immune checkpoint markers CD274 and CTLA4, along with increased tumor-infiltrating lymphocytes (TILs), particularly CD4+ T cells. The study also identified higher expression of immunosuppressive markers such as CD73 and CD200 expressed by tumor cells, which could be promising targets for immunotherapy. Experiments with PTC cell lines demonstrated that Dabrafenib-mediated BRAF inhibition induces CD274 expression. Further, these PTC cells with induced CD274 expression are more susceptible to immune-mediated cell killing. The findings suggest that BRAF inhibition could potentiate tumor cells for immunotherapy and boost the tumor-killing effect. <h3>Conclusions</h3> The findings indicate that PTC cases with BRAF mutations or high BRAF expression may be associated with an immune hot signature, potentially benefiting from immunotherapeutic strategies.