Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many
cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in
cancer, but both patients and
tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of
tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to
immunotherapy. We show that the murine
tumor lines B16 and MC38 differed in their ability to consume
oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade.
Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in
tumor cells in vitro and in vivo, resulting in reduced intratumoral
hypoxia. Although
metformin monotherapy had little therapeutic benefit in highly aggressive
tumors, combination of
metformin with PD-1 blockade resulted in improved intratumoral T-cell function and
tumor clearance. Our data suggest tumor hypoxia acts as a barrier to
immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to
immunotherapy into those that receive clinical benefit.
Cancer Immunol Res; 5(1); 9-16. ©2016 AACR.