Differential immune pathways in classic and mixed variants of anaplastic thyroid cancer.

Abstract

e18579 Background: Patients with anaplastic thyroid cancer (ATC) have poor outcomes due to treatment resistance with an estimated 5-year survival rate of 7%. Although “classic” ATC can arise de novo from follicular thyroid cells, it can also arise in association with papillary thyroid carcinoma (PTC), as a “mixed” histology. The immunologic and molecular differences between these histological subtypes have not been well-characterized. We aimed to investigate the differences in immune signatures in these histological subtypes to assess immune pathway differences in the classic ATC and mixed ATC/PTC tumor microenvironment. Methods: Classic ATC and mixed ATC/PTC cases (N = 12) from 1998 to 2018 with viable formalin-fixed paraffin-embedded (FFPE) tissue were identified and selected by a board-certified pathologist. 4 samples exhibited both PTC and ATC components while 8 were classic ATC cases, as confirmed by a pathologist. In the 4 mixed ATC/PTC histology specimens, 3 were identified to contain greater than 80% ATC involvement while the fourth was characterized as 40% ATC and 60% PTC. The NanoString Immune Profiling panel contains more than 770 genes. It was performed with extracted RNA to evaluate and compare the gene expression of classic ATC versus mixed ATC/PTC. Results: Majority of patients (N = 11) developed metastatic disease, a common feature of ATC, and are currently deceased (N = 10). The NanoString panel identified several differentially expressed immune pathways in the mixed ATC/PTC in comparison to the classic ATC group. There is upregulation of CD3 (p < 0.01) and CD8 (p < 0.01) transcripts in the mixed ATC/PTC group, but not CD4 transcripts (p > 0.05). Additionally, we found that genes associated with B cell and T cell function were significantly upregulated in the mixed ATC group, including CD27 (p < 0.01), CD28 (p < 0.05), BTLA (p < 0.01), CTLA4 (p < 0.01), LAG3 (p < 0.05), and TIGIT(p < 0.01). We did not observe any significant differences in the expression of PD1 (p > 0.05) or MR1 (p > 0.05) between classic ATC and mixed ATC variants. Conclusions: Our study demonstrates a significant difference in the immune landscape between classic and mixed variants of ATC. Our results indicate there may be an increase in immune cell infiltration and tumor inflammation in the mixed ATC variant, which suggests patients with the mixed ATC variant may show a positive response to immunotherapy.