Metabolism and Immune Modulation in Patients with Solid Tumors: Systematic Review of Preclinical and Clinical Evidence

Abstract

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients’ nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.

Harnessing Biomaterials to Study and Direct Antigen-Specific Immunotherapy

“…These types of therapies are used clinically to treat solid tumors, with 17 clinical studies completed as of 2020. 36 As suggested in previous sections, combining this approach with materials could enable more effective manipulation of metabolic pathways in immune cells to drive stronger therapeutic outcomes. However, one challenge associated with metabolic cargo is that these are often small compounds that require a high effective concentration to drive immunomodulatory effects.…”

“…As a result, delivery of immunometabolic cargo has emerged as potential way to revolutionize immunotherapy. These types of therapies are used clinically to treat solid tumors, with 17 clinical studies completed as of 2020 . As suggested in previous sections, combining this approach with materials could enable more effective manipulation of metabolic pathways in immune cells to drive stronger therapeutic outcomes.…”

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

“…In murine B16 and MC38 melanoma models, combining anti-PD-1 treatment with metformin significantly reduced tumor growth by metabolic remodeling, reduced tumor hypoxia and improved T cell infiltration and function, as compared to either treatment alone (141). This combination treatment is currently under investigation in human clinical trials for advanced melanoma and non-small cell lung cancer (NSCLC) (NCT04114136) (142). Further, metformin can induce PD-L1 glycosylation and degradation thereby enhancing CTL activity and improving the efficacy of immunotherapy (143).…”

Ornithine α-Ketoglutarate Alleviates Inflammation via Regulating Ileal Mucosa Microbiota and Metabolites in Enterotoxigenic Escherichia coli-Infected Pigs

“…Ornithine α-ketoglutarate (OKG) is a nutritional compound that consists of one molecule of α-ketoglutarate and two molecules of ornithine, a precursor of glutamine, arginine, and proline, which benefit the immune response by altering inflammatory processes during times of challenge ( 8 – 12 ). More specifically, OKG improves glutamine in blood and has antitumor functions in combination with the glutaminase 1 enzyme pathway inhibitors ( 8 ). In recent years, OKG in stock farming has attracted growing attention.…”

“…In recent years, OKG in stock farming has attracted growing attention. For instance, in ovo , 0.2 or 0.4% of OKG injection can promote early growth and pectoral muscles of chicks ( 8 ). Administration of 0.4 g/kg of OKG improves bone properties and amino acid synthesis in rapidly growing turkeys ( 13 ).…”