Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy

Abstract

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.

Keywords: T cell antitumor immunity; cancer immunotherapy; creatine; metabolic regulator.

Figure 1

The “hybrid-engine” model in T cell antitumor immunity and potential application of creatine supplementation for cancer immunotherapy. (A) Limited nutrients for immune cells in the tumor microenvironment. (B) The “hybrid-engine” model. Analogous to the hybrid car, a tumor antigen-specific CD8 T cell uses a “molecular fuel engine”, including tricarboxylic acid cycle and glycolysis, to convert nutrients into adenosine triphosphate (ATP), while utilizing creatine-mediated energy buffering system, a “molecular battery”, to store ATP and power T cell activities. (C) Creatine can be obtained from creatine-rich diet (e.g., red meat, poultry, and fish) and dietary supplements. (D) Creatine administration as a therapeutic intervention would result in the best therapeutic effects. ©2019 Di Biase et al. Originally published in J. Exp. Med. doi: 10.1084/jem.20182044.