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Targeting metabolism to regulate immune responses in autoimmunity and cancer

Nature Reviews Drug Discovery volume 18, pages 669–688 (2019)Cite this article

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Abstract

Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of ‘cellular selectivity based on demand’, in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.

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Fig. 1: Metabolic determinants of immune cell differentiation and function.
Fig. 2: Metabolic phenotypes of immune cells involved in acute immune responses.
Fig. 3: Selected strategies to target metabolism to regulate T cell function in diseases.

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Acknowledgements

The authors thank members of the Powell laboratory for critical review of the manuscript. The authors are supported in part by National Institutes of Health (grants T32AI007247 and T32HL007227 to C.H.P. grant R01HL141490 to M.R.H. and grants R01AI077610, R01CA226765 and R01CA229451 to J.D.P.) and the Bloomberg~Kimmel Institute of Cancer Immunotherapy (J.D.P.).

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  1. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Chirag H. Patel, Robert D. Leone & Jonathan D. Powell

  2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Maureen R. Horton

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J.D.P. has equity in Dracen, Sitryx (<5%) and Corvus (<5%); has consulted for Dracen, as well as for Sitryx, Corvus, Aeonian, Sigma and Quadriga; has received sponsored research money from Abbvie, Quadriga, Dracen, Bluebird and Bristol-Myers Squibb in the last year; and has patents licensed by Dracen. The other authors declare no competing interests.

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Glossary

Signal 1

T cell receptor engagement of peptide–major histocompatibility complex.

Co-stimulation

A ligand–receptor signal provided by activated antigen-presenting cells (for example, B7-1 on antigen-presenting cells engaging CD28 on T cells) that leads to full T cell activation.

Tolerant T cells

T cells that receive signal 1 (T cell receptor engagement) in the absence of co-stimulation are deleted or become anergic (tolerant) such that they fail to become fully activated on subsequent rechallenge.

Regulatory T cells

(Treg cells). FOXP3+CD4+ T cells that negatively regulate immune responses and thus play an important role in preventing overexuberant inflammation and autoimmunity.

Effector Treg cells

While circulating regulatory T cells (Treg cells) are relatively metabolically quiescent, on activation such cells become FOXP3+CD44hiCD62lomTORC1hi effector Treg cells (mTORC1 is mechanistic target of rapamycin complex 1) that are responsible for actively suppressing inflammatory/immune responses.

IL-17-producing T helper cells

(TH17 cells). Characterized by the production of the proinflammatory cytokine IL-17, TH17 cells contribute to pathogen clearance at mucosal surfaces, but have also been implicated in autoimmune and inflammatory disorders.

M1 macrophages

Known as ‘classically activated macrophages’, these cells protect against bacteria and viruses by producing proinflammatory cytokines and by phagocytizing and killing microorganisms by generating nitric oxide or reactive oxygen species.

M2 macrophages

Known as ‘alternatively activated macrophages’, these cells are associated with wound healing and tissue repair by inducing proliferation or collagen deposition.

Myeloid-derived suppressor cells

A myeloid-derived heterogeneous group of immature macrophages and granulocytes that actively suppress antitumour T cell responses.

Trained immunity

The ability of the innate immune system to mount an enhanced memory response on reinfection.

Induced Treg cells

FOXP3+CD4+ regulatory T cells (Treg cells) that are generated when naive CD4+ T cells are stimulated under suppressive conditions (such as in the presence of transforming growth factor-β).

B6.Sle1.Sle2.Sle3 (TC) lupus-prone mouse model

A spontaneous mouse model of systemic lupus erythematosus that mimics human disease due to increased levels of autoantibodies and activated CD4+ T cells.

Plasmablasts

Antibody-secreting B cells in lymph nodes that demonstrate some features of a plasma cell but are typically short-lived compared with differentiated plasma cells.

KBN mouse model

A spontaneous model of arthritis caused by the activation of T cell receptor transgenic CD4+ T cells from the KRN strain and glucose 6-phosphate isomerase peptides presented by the H-2g7 allele.

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Patel, C.H., Leone, R.D., Horton, M.R. et al. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat Rev Drug Discov 18, 669–688 (2019). https://doi.org/10.1038/s41573-019-0032-5

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