Myoglobin expression improves T-cell metabolism and antitumor effector function.

backgroundThe tumor microenvironment is frequently hypoxic and characterized by a scarcity of nutritional resources including a shortage of glucose. As effector T cells have high energy demands, tumor metabolism can contribute to T-cell dysfunction and exhaustion.

methodsIn this study, we determined hypoxia in spleen and tumor tissue from tumor-bearing C57BL/6J mice using reverse transcription polymerase chain reaction (RT-PCR), histology and flow cytometry. Next, CD8

resultsHere we demonstrate that expression of the oxygen-binding protein myoglobin in T cells can boost their mitochondrial and glycolytic metabolic functions. Metabolites and tricarboxylic acid compounds were highly increased in the presence of myoglobin (Mb), which was associated with increased ATP levels. Mb-expressing T cells exhibited low expression of hypoxia-inducible factor-1α after activation and during infiltration into the tumor microenvironment (TME). Accordingly, Mb expression increased effector T-cell function against tumor cells in vitro with concomitant reductions in superoxide levels. Following adoptive transfer into tumor-bearing mice, Mb expression facilitated increased infiltration into the TME. Although T cells expressing Mb exhibited increased expression of effector cytokines, PD-1 was still detected and targetable by anti-PD-1 monoclonal antibodies, which in combination with transfer of Mb-expressing T cells demonstrated maximal efficacy in delaying tumor growth.

conclusionTaken together, we show that expression of Mb in T cells can increase their metabolism, infiltration into the tumor tissue, and effector function against cancer cells.