Abstract
T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine supplementation with a PD-1/PD-L1 blockade treatment showed synergistic tumor suppression efficacy. We further demonstrated that creatine acts as a "molecular battery" conserving bioenergy to power T cell activities. Therefore, our results have identified creatine as an important metabolic regulator controlling antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell-based cancer immunotherapies.
Highlights
T cells play a central role in mediating and orchestrating immune responses against cancer; they are attractive therapeutic targets for treating cancer (Couzin-Frankel, 2013; Page et al, 2014; Ribas, 2015; Rosenberg and Restifo, 2015; Baumeister et al, 2016; Lim and June, 2017)
We found that tumor-infiltrating immune cells (TIIs) up-regulated their expression of the creatine transporter gene (Slc6a8 or Creatine transporter gene (CrT)), which encodes a surface transporter controlling the uptake of creatine into a cell (Wyss and Kaddurah-Daouk, 2000)
In addition to the change of genes involved in the classic glucose/lipid/amino acid metabolic pathways (Fox et al, 2005), we detected a sharp increase of the expression of a CrT (Slc6a8) gene in TIIs (Fig. 1 A)
Summary
T cells play a central role in mediating and orchestrating immune responses against cancer; they are attractive therapeutic targets for treating cancer (Couzin-Frankel, 2013; Page et al, 2014; Ribas, 2015; Rosenberg and Restifo, 2015; Baumeister et al, 2016; Lim and June, 2017). An efficient and economical bioenergy metabolism is needed for tumor-infiltrating T cells to mount and sustain effective anticancer responses (Siska and Rathmell, 2015). We show that creatine is a critical molecule buffering ATP levels in cancer-targeting CD8 T cells through maintaining a readily available high-energy phosphate reservoir (Wyss and Kaddurah-Daouk, 2000). We found that tumor-infiltrating immune cells (TIIs) up-regulated their expression of the creatine transporter gene (Slc6a8 or CrT), which encodes a surface transporter controlling the uptake of creatine into a cell (Wyss and Kaddurah-Daouk, 2000). Our results have identified creatine as an important “molecular battery” that conserves bioenergy to enhance antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell–based cancer immunotherapies
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