Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy

Abstract

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

“…This interaction has gained recognition as a hallmark of cancer and immunotherapy has become an established pillar of cancer therapy [ 1 ]. Immune cells execute their function most effectively when they are able to respond swiftly to environmental stimuli through phenotypic shifts, enhanced by the radical reprogramming of immune cell metabolism [ 92 ]. On the other hand, impaired metabolic flexibility results in an ineffective anti-tumour immune response, and may be explained by the mutual metabolic requirements of immune cells and tumour cells, which compete for similar essential nutrients such as glucose and glutamine.…”

“…Altered tumour metabolism can promote chromatin remodelling and epigenetic modifications in multiple ways, such as by supplying acetyl and methyl groups and producing metabolites that act as key cofactors or inhibitors of epigenetic enzymes, such as α-KG, succinate, fumarate, and 2-hydroxyglutarate [ 147 ]. Furthermore, the enhanced nucleotide biosynthesis in tumours promotes DNA repair [ 92 ]. Taken together, these processes lead to a reduced mutation rate and, hence, reduced tumour antigenicity, thereby limiting the effectiveness of immunotherapies.…”

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

“…The fact that PD-L1 protects cancer cells from immune-mediated cell death via activation of the PI3K/AKT pathway and mTOR [ 108 ] supports the notion that dysregulated cancer cell-autonomous metabolism might represent a two-way barrier against antitumor immunity. Also, pyruvate kinase muscle 2 (PKM2), the alternative splicing form of PKM that enables exacerbated aerobic glycolysis in cancer cells, has been shown to directly promote the expression of PD-L1 in cancer cells [ 109 , 110 ]. Further, select metabolic activities and metabolites might enable cancer cells to simultaneously drive immunologically relevant decisions on both immune and tumor cell compartments.…”

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

“…Immune metabolism plays an important role in the immune response to malignancy. The dysregulation of immune metabolism can affect immune surveillance either at the cellular level or at the systemic host level, leading to lower ICI efficacy and primary or acquired resistance to immune checkpoint inhibition [ 213 ]. Dysregulation at the cellular level includes some of the mechanisms and pathways previously discussed, such as the VEGF, tryptophan and PI3K/AKT/mTOR pathways, or the stimulation of immunosuppressive cells such as TAMs or MDSCS and the inhibition of effector T-cells in the tumor micro-environment, as will be further elaborated on.…”