Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response

Abstract

We are living a time of renaissance in metabolism research, which touches many fields of basic research and clinical medicine. While research in cancer metabolism has been at the forefront of this since the early 2000s, a more recent focus has been how metabolism underpins many key aspects of immune function. After over a decade of research in this field of immunometabolism, which has deepened our understanding of the basic processes which intertwine metabolic to signalling pathways in the control of adaptive and innate immunity, the time has come to translate these discoveries into clinical settings [1,2]. Here we have collected a series of reviews from some of the groups that, around the world, are pushing these boundaries to fill the gaps between bench and bedside in this exciting area of the research.Pallet, Schmidt and Schurich [3] discuss the metabolic profile of T lymphocytes responding to viral infections and more specifically how in the context of chronic viral infection, pathogen-specific T cells demonstrate functional insufficiency often associated with a dysregulated metabolic phenotype. They describe recent findings from both human studies and animal models investigating the link between these two observations, the mechanisms involved and, importantly, in vitro or in vivo treatments which have both corrected the dysregulated metabolic phenotype and restored T cell immune competence. Additionally, they discuss the fascinating way in which certain viruses have evolved the capacity to alter the metabolism of the cells they infect to support viral replication, which may translate into novel anti-viral therapeutics.Yu and Ho [4] describe how the tumour microenvironment (TME) impacts T cell metabolism and interlinked immune function, for example via nutrient restriction, increased immune checkpoint signalling, altered pH, metabolite accumulation and hypoxia. Furthermore, they describe novel therapeutic strategies aiming either to correct the immunosuppressive TME via targeting metabolic pathways and enzymes, or to rewire T cells themselves to increase their "metabolic tolerance". Very interestingly, they also propose a novel hypothesis whereby (akin to tumour immunoediting) the immune response to a tumour may indeed evolve the metabolic profile of the tumour -i.e. that "the host immune system eradicates ……. metabolically unfit cancer cells, which fail to abolish the metabolic fitness of anti-tumour immune cells". Such a process would select for tumour cells that exacerbate the TME for effector immune cells, while simultaneously favouring recruitment and activity of immunosuppressive populations, for which this environment is favourable. They continue to discuss how, if such a model is proved to be true, this may identify novel therapeutic targets or strategies to skew the TME into a metabolically supportive environment for anti-tumour immunity.Loetscher and Balmer [5] discuss how activity of the immune system is not only regulated by the detection of pathogenic or host-derived threats, via surface or Clini...