Abstract 628: Immunometabolic signature of papillary thyroid carcinoma

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Abstract Introduction: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer with rapidly rising incidence. The interface between PTC tumor metabolic reprogramming and metabolic immunomodulation remains poorly understood. Experimental Procedures: We sought to investigate the immunometabolic interaction patterns of PTC tumors and to determine whether a correlative relationship exists between tumor-infiltrating immune cell phenotypes and the expression of tumor metabolic enzymes. We performed a computational immunogenomic analysis to calculate leukocyte fractions within 496 PTC tumors from The Cancer Genome Atlas (TCGA). Immunogenomic analysis was performed using CIBERSORT (Newman AM et al., Nature Methods2015), a deconvolution method to calculate leukocyte fractions using RNA gene expression signatures. The PTC immune cell fractions were then compared to the RNA expression of tumor metabolic enzymes within the TCGA data using regression analysis. Matching targeted metabolomic analysis (Metabolon, Inc.) of 20 human PTC tumors was performed to determine tumor metabolite profiles associated with perturbed tumor cellular metabolic pathways based on the TCGA data analysis. Results: The immunogenomic and PTC metabolic pathway enzyme expression analysis demonstrated significant correlation between immune cell types and major metabolic pathway enzymes. Specifically, tumor glycolytic enzymes upstream of the TCA cycle correlated with CD8 (hexokinase-1, p<0.0001) and T regulatory (enolase, p<0.0001) cell infiltrates. Enhanced pyruvate cycling into the TCA cycle correlated with the presence of several immune cell types (malic enzyme 2 vs. follicular helper T cells, p<0.0001; pyruvate carboxylase vs CD8 T cells, p<0.0001). The expression of TCA cycle enzymes correlated with the fraction of macrophages (aconitase, p<0.0001; IDH1, p<0.05). Significant differences in PTC tumor and normal thyroid tissue metabolite profiles were observed in glycolysis and TCA cycle, further supporting our findings of immunometabolic plasticity it PTC. Together, these findings highlight the central role TCA cycle activity plays in PTC tumor immunometabolism. Conclusion: We demonstrate, for the first time, a distinct immunometabolic tumor signature supported by tumor metabolic reprogramming in PTC tumors. This novel characterization approach provides an important foundation for future functional metabolic studies within the tumor and immunologic microenvironment. A mechanistic understanding of the complex integration of immune networks and cellular metabolism can be harnessed for future therapeutic immunometabolic modulation in PTC. Citation Format: Vivian L. Weiss, Naira Baregamian. Immunometabolic signature of papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 628.