Abstract 1902: Elevated thymidine kinase 1 (TK1) in cancer serum may suppress immune function

Abstract

Abstract In this project, we wanted to investigate the role that TK1 may play in macrophage activation and immune suppression. The relationship between immune response and cancer development has been an enigma that researchers have sought to elucidate for decades. Recent and past studies have suggested that the presence and abundance of nucleotides can affect immune response. Thymidine Kinase 1 (TK1) is a salvage pathway enzyme that converts thymidine to thymidine monophosphate, a precursor to DNA synthesis. It is secreted into serum and as such has been suggested to be a tumor biomarker. TK1 has also shown to be present on the surface of many different cancer cell lines including breast, lung, and colorectal cancer. The reason for this upregulation of surface TK1 is unclear, but it has been suspected that the surface expression of TK1 may be beneficial to tumor growth and survival since high TK1 expression and secretion is an early event in tumorigenesis. Although the immunosuppressive properties of purines have been well established, pyrimidines such as thymidine have not been studied as potential immune suppressants. In our investigation, we first confirmed the increased surface expression levels of TK1 in cancerous cell lines. Flow cytometry showed that non-cancerous cells expressed surface TK1 at minimal levels (0.7%), MDA-MB-231 cells expressed TK1 at higher levels (45%), and PC3 cells expressed TK1 at elevated levels as well (64.6%). Bioinformatic analysis of nucleotide transport in relation to TK1 surface expression showed a strong positive correlation between the nucleotide transporter SLC29A2 and surface TK1 expression in colon adenocarcinoma (correlation value 0.455, p-value <0.001), head and neck squamous cell carcinoma (correlation value 0.416, p-value <0.001), rectum adenocarcinoma (correlation value 0.432, <0.001), stomach adenocarcinoma (correlation value 0.405, p-value <0.001), and uterine corpus endometrial carcinoma (correlation value 0.403, p-value <0.001) which further confirms the elevation of TK1 on the surface of cancer cells and suggests a mechanism whereby serum TK1 levels are elevated. Macrophage engulfment assays were then conducted in order to investigate the possibility that exposure to higher concentrations of TK1 leads to immune suppression. We found that macrophages differentiated from THP-1 monocytes that were exposed to varying concentrations of TK1 for 24 hours showed a decrease in macrophage engulfment (29%-37%) compared to controls that were not exposed to TK1(61.2%). These results suggest that TK1 may have some involvement in immune suppression during cancer development, and we intend to further investigate these findings. Citation Format: Kathryn R. Smith, Rachel M. Morris, Edwin J. Velazquez, David M. Bellini, Kim O'Neill. Elevated thymidine kinase 1 (TK1) in cancer serum may suppress immune function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1902.