Cancer cell metabolism and antitumour immunity

Abstract

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

Figure 1.. Glucose, lactate, and intermediate metabolism in anticancer immunity.

The bioenergetic metabolism of cancer cells, characterized by increased glucose uptake coupled with abundant lactate secretion as well as alterations in the tricarboxylic acid (TCA) cycle has a major impact on the immunological tumor microenvironment (TME). For instance, an increased glycolytic flux in cancer cells has been associated with the NF-κB-dependent upregulation of PD-L1 and the secretion of myeloid-derived suppressor cell (MDSC)-recruiting cytokines like GM-CSF and M-CSF, as well as with the reduced release of the cytotoxic T lymphocyte (CTLs)-recruiting and pro-inflammatory chemokine CXCL10. Along similar lines, microenvironmental lactate has been shown to limit the proliferation and activation of CTLs and natural killer (NK) cells while promoting the recruitment and immunosuppressive function of regulatory T (T_REG) cells and tumor-associated macrophages (TAMs). Finally, mitochondrial alterations emerging from TCA cycle defects have been linked with the secretion of metabolic intermediates with direct CTL-suppressive effects, including fumarate and D-2-hydroxyglutarate (D-2HG), as well as with the cytosolic accumulation of cytosolic mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), instead culminating with the secretion of immunostimulatory type I interferon (IFN). DC, dendritic cell.

Figure 2.. Fatty acid and eicosanoid metabolism on anticancer immunity.

Cancer cells generally exhibit an increase in both fatty acid (FA) intake from the tumor microenvironment (TME) and endogenous fatty acid synthesis. This results in immunomodulatory effects emerging from (1) increased MHC Class I exposure on the cancer cell surface, resulting in improve recognition by cytotoxic T lymphocytes (CTLs), (2) elevated CD47 expression, limiting phagocytic uptake by myeloid cells; and (3) inhibited immunogenic cell death (ICD), preventing pronounced dendritic cell (DC) activation. Moreover, high levels of FAs in the TME have a direct immunosuppressive effect on CTLs and DCs, coupled with an increased in regulatory T (T_REG)-mediated immunosuppression. Finally, cancer cells can convert FAs stored as lipid droplets into immunosuppressive eicosanoids such as prostaglandin E2 (PGE₂). NK, natural killer.

Figure 3.. Nucleotide and amino acid metabolism in anticancer immunity.

Alterations in the urea cycle promote cancer cell immunogenicity by favoring the expression of tumor-associated antigens (TAA), while ATP released in the context of immunogenic cell death (ICD) mediates potent chemotactic and immunostimulatory effects on myeloid cells that are actively counteracted when extracellular ATP is converted into immunosuppressive adenosine by CD39 and CD73. Increased glutamine metabolism favors the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) by promoting CD47 and IDO1 upregulation. Methionine uptake by cancer cells promotes cytotoxic T lymphocyte (CTL) exhaustion via 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) as it inhibits type I interferon (IFN) secretion by methylating CGAS. Tryptophan degradation as mediated in cancer cells and myeloid cells by IDO1 results in the accumulation of immunosuppressive metabolites including kynurenine. Finally, lysine has been shown to suppress type I IFN production by malignant cells upon histone H4 lysine crotonylation. DC, dendritic cell; T_REG, regulatory T; UCD, urea cycle dysregulation.