Targeting the metabolism of tumor-infiltrating regulatory T cells

Abstract

Metabolic restrictions in the tumor microenvironment (TME) can force immune cells to develop a tolerant phenotype for metabolic adaptation, ultimately impairing the antitumor effectiveness of immune cells and immunotherapies.Drugs that target tumor metabolism have slowly progressed because of possible nonspecific targeting.Regulatory T cells (Tregs) are unique in terms of their immune and metabolic features. They limit the intensity of the immune response and can promote tumors’ immune escape. They can use lactic acid as a fuel and shift to more efficient oxidative phosphorylation to avoid metabolic restrictions in the TME, reinforcing their function.Future efforts to improve the antitumor immune response might overcome the harmful effects of metabolic restrictions and tumor-infiltrating Tregs (TI-Tregs) and their interactions with the TME. Because tumor cells share some metabolic profiles with TI-Tregs, targeting the metabolism of TI-Tregs might have immune and metabolic benefits. Recent trials have noted that the tumor metabolism can hamper the efficacy of immunotherapy; however, the indiscriminate targeting of the tumor metabolism fails to achieve the desired outcomes because of the disturbance of metabolically reprogrammed immune cells, especially immunosuppressive regulatory T cells (Tregs). Tumor-infiltrating Tregs are restricted to a greater immunosuppressive state by tumor metabolites such as lactate, fatty acids (FAs), and kynurenine, which are intolerable to other immune cells. Therefore, targeting the metabolism of tumor-infiltrating Tregs has immune and metabolic significance, and might represent a candidate approach to overcome metabolic obstacles during immunotherapy. Seventy years after Sidney Farber introduced antifolate drugs to treat childhood leukemia, targeting tumor metabolism has regained attention with the rise of cancer immunotherapy (see Glossary) [1.Stine Z.E. et al.Targeting cancer metabolism in the era of precision oncology.Nat. Rev. Drug Discov. 2022; 21: 141-162Crossref PubMed Scopus (183) Google Scholar]. Metabolic restrictions in the TME, such as hypoxia, low nutrient availability, and highly suppressive metabolites, have led to obstacles to immunotherapeutic approaches [2.DePeaux K. Delgoffe G.M. Metabolic barriers to cancer immunotherapy.Nat. Rev. Immunol. 2021; 21: 785-797Crossref PubMed Scopus (147) Google Scholar]. One question in the field has been whether targeting the tumor metabolism might lead to both tumor-limiting and immunity-promoting benefits. Recent clinical trials targeting the tumor metabolism have shown disparate responses, partly because assessing the metabolic profiles of infiltrating immune cells has been neglected [1.Stine Z.E. et al.Targeting cancer metabolism in the era of precision oncology.Nat. Rev. Drug Discov. 2022; 21: 141-162Crossref PubMed Scopus (183) Google Scholar,3.Elia I. Haigis M.C. Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism.Nat. Metab. 2021; 3: 21-32Crossref PubMed Scopus (150) Google Scholar]. To resolve possible conflicts between metabolism and immunity, the concept of immunometabolism has been emphasized in immune-oncology fields to provides pivotal insights into potential regulators and reprogramming pathways of immune cell populations [4.Artyomov M.N. Van den Bossche J. Immunometabolism in the single-cell era.Cell Metab. 2020; 32: 710-725Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar,5.Bader J.E. et al.Targeting metabolism to improve the tumor microenvironment for cancer immunotherapy.Mol. Cell. 2020; 78: 1019-1033Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. However, it remains unclear which infiltrating immune cells, including tumor-associated macrophages, T and B cells, dendritic cells, and myeloid suppressor cells, are responsible for these unexpected outcomes. Single-cell techniques have revealed metabolic heterogeneity among immune cells, including Tregs, which have a distinctive metabolism and immunosuppressive abilities [4.Artyomov M.N. Van den Bossche J. Immunometabolism in the single-cell era.Cell Metab. 2020; 32: 710-725Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]. Tregs comprise 5–15% of the CD4+ T cells and promote the immunotolerance of malignant cells, leading to unfavorable prognoses for multiple cancers [6.Shan F. et al.Therapeutic targeting of regulatory T cells in cancer.Trends Cancer. 2022; 8: 944-961Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Treg-targeting drugs such as kinase inhibitors, anti-CD25, antichemokine (C-C motif) receptor 4 (CCR4), anti-CCR8, anti-T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT), and anti-interleukin (IL)-10 are nonspecific and may have side-effects within the immune system that could lead to the development of autoimmune diseases [6.Shan F. et al.Therapeutic targeting of regulatory T cells in cancer.Trends Cancer. 2022; 8: 944-961Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Therefore, to enhance the potential of Treg-targeted therapies and ideally restore the efficacy of targeting the tumor metabolism, it is necessary to analyze the metabolic profiles of TI-Tregs (Figure 1) and their transformation during migration, proliferation, and functioning (Box 1 and Figure 2).Box 1Metabolic changes in Tregs during migration, proliferation, and functionGlycolysis contributes to the migration of TregsCD28 activates glycolysis mediated by PI3K–AKT–mTORC2 to upregulate glucokinase (GCK), which interacts to enhance cytoskeletal rearrangements during migration in vitro [56.Kishore M. et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis.Immunity. 2017; 47: 875-889Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Additionally, the PI3K–AKT–mTORC2 the migration of Tregs to impairing their to and which and receptor 1 et al.Regulatory T cell and migration are dependent on Immunol. 2020; PubMed Scopus Google Scholar]. a has been to target the migration of Tregs in et and T cell immune PubMed Scopus (0) Google Scholar]. that migration can by and by with that might to the is metabolic for and such as kinase kinase and a in et of metabolism in T and Immunol. 2017; 8: PubMed Scopus Google et fatty acid the between regulatory T and T PubMed Scopus Google et by metabolism is a for suppressive Metab. 2020; Full Text Full Text PDF PubMed Scopus Google K. et of metabolic and of cells by 2017; PubMed Scopus (0) Google Scholar]. a the of Tregs by et and oxidative metabolic are for and regulatory CD4+ T cell Immunol. PubMed Scopus Google Scholar]. However, the of on the and of Tregs and Tregs, that can Tregs by other et on regulatory and T cells are of fatty acid Metab. Full Text Full Text PDF PubMed Scopus Google Scholar]. as a metabolic and activates which for et pathways in regulatory T cell Immunol. PubMed Scopus Google Scholar]. from the of by and from Additionally, to and to M. et of is for of T Full Text Full Text PDF PubMed Scopus (0) Google et of regulatory T cell and by 2017; PubMed Scopus Google Scholar]. that the of Tregs is by which is by multiple such as and and to the glycolysis to et and receptor T cell metabolism for Immunol. PubMed Scopus (0) Google Scholar]. and from to the of Tregs and Tregs to the of the of T cells to the of to et are for T cell Full Text Full Text PDF PubMed Scopus Google Scholar]. by by in the regulatory of the et of in regulatory T cell and Full Text Full Text PDF PubMed Scopus Google et is for suppressive of regulatory T PubMed Scopus Google Scholar]. and the to enhance and by and M. et of is for of T Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. the of in Tregs cellular et by metabolism is a for suppressive Metab. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar]. that can by the of which could metabolic pathways during the migration, proliferation, and of regulatory T cells migration, Tregs receptor 4 and to in the tumor microenvironment (TME) [6.Shan F. et al.Therapeutic targeting of regulatory T cells in cancer.Trends Cancer. 2022; 8: 944-961Abstract Full Text Full Text PDF PubMed Scopus (0) Google M. et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis.Immunity. 2017; 47: 875-889Abstract Full Text Full Text PDF PubMed Scopus (131) Google et al.Regulatory T cell and migration are dependent on Immunol. 2020; PubMed Scopus Google et and T cell immune PubMed Scopus (0) Google Scholar]. kinase B target of glycolysis by glucokinase (GCK), which interacts with to enhance cytoskeletal rearrangements [56.Kishore M. et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis.Immunity. 2017; 47: 875-889Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. and receptor 1 by the and et al.Regulatory T cell and migration are dependent on Immunol. 2020; PubMed Scopus Google Scholar]. and Tregs glycolysis fatty acid et on regulatory and T cells are of fatty acid Metab. 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PubMed Scopus (0) Google et are for T cell Full Text Full Text PDF PubMed Scopus Google Scholar]. fatty acid fatty of T receptor and fatty acid Figure contributes to the migration of Tregs activates glycolysis mediated by PI3K–AKT–mTORC2 to upregulate glucokinase (GCK), which interacts to enhance cytoskeletal rearrangements during migration in vitro [56.Kishore M. et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis.Immunity. 2017; 47: 875-889Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Additionally, the PI3K–AKT–mTORC2 the migration of Tregs to impairing their to and which and receptor 1 et al.Regulatory T cell and migration are dependent on Immunol. 2020; PubMed Scopus Google Scholar]. a has been to target the migration of Tregs in et and T cell immune PubMed Scopus (0) Google Scholar]. that migration can by and by with that might to the Tregs is metabolic for and such as kinase kinase and a in et of metabolism in T and Immunol. 2017; 8: PubMed Scopus Google et fatty acid the between regulatory T and T PubMed Scopus Google et by metabolism is a for suppressive Metab. 2020; Full Text Full Text PDF PubMed Scopus Google K. et of metabolic and of cells by 2017; PubMed Scopus (0) Google Scholar]. a the of Tregs by et and oxidative metabolic are for and regulatory CD4+ T cell Immunol. PubMed Scopus Google Scholar]. However, the of on the and of Tregs and Tregs, that can Tregs by other et on regulatory and T cells are of fatty acid Metab. Full Text Full Text PDF PubMed Scopus Google Scholar]. as a metabolic and activates which for et pathways in regulatory T cell Immunol. PubMed Scopus Google Scholar]. from the of by and from Additionally, to and to M. et of is for of T Full Text Full Text PDF PubMed Scopus (0) Google et of regulatory T cell and by 2017; PubMed Scopus Google Scholar]. that the of Tregs is by which is by multiple such as and and to the glycolysis to et and receptor T cell metabolism for Immunol. 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