Control of the Antitumor Immune Response by Cancer Metabolism

Abstract

The metabolic reprogramming of tumor cells and immune escape are two major hallmarks of cancer cells. The metabolic changes that occur during tumorigenesis, enabling survival and proliferation, are described for both solid and hematological malignancies. Concurrently, tumor cells have deployed mechanisms to escape immune cell recognition and destruction. Additionally, therapeutic blocking of tumor-mediated immunosuppression has proven to have an unprecedented positive impact in clinical oncology. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune signaling through both the release of signaling molecules and the expression of immune membrane ligands. Here, we review these molecular events to highlight the contribution of cancer cell metabolic reprogramming on the shaping of the antitumor immune response.

Keywords: cancer; immunity; metabolism.

Figure 1

Cancer cell metabolism. Most cancer cells depend on a higher glycolytic metabolism to proliferate and disseminate, regardless of the presence of oxygen. This is made possible through the overexpression of GLUT1, a glucose cell surface transporter. This metabolic switch, known as the Warburg effect, occurs at the expense of the oxidative phosphorylation (OXPHOS) and provides, in a short amount of time, the energy, as well as many precursors of the macromolecules, required to sustain a high rate of proliferation. In cancer cells, pyruvate is largely directed to produce lactate instead of being metabolized within mitochondria. Glutamine and fatty acids constitute two other substrates used preferentially by tumor cells, and which provide intermediates of the tricarboxylic acid cycle (TCA) cycle. They are further used to produce other building blocks for these demanding cells and to maintain some mitochondrial activity and functioning.

Figure 2

Cancer cells induced-lactate and -proton release within the peritumoral environment and the consequences for immune cell function. The metabolic switch towards aerobic glycolysis observed in most cancer cells (i.e., Warburg’s effect) produces significant amounts of pyruvate that are mostly metabolized into lactate. The intracellular increase of lactate, potentially toxic for the cancer cell, is then released into the extracellular medium together with protons (thanks to transporters such as MCT4), inducing an acidification of the local environment. The frequent up-regulation of carbonic anhydrase IX (CA-IX) in cancer cells also contributes to the local increase of H+ in the immediate neighborhood of cancer cells. Both, the accumulation of lactate and the decrease in the pH of the extracellular milieu create a detrimental environment for the antitumoral immune response, (i) decreasing the function of the CD8+ T cells, dendritic cells (DCs), monocytes, natural killer (NK) cells and/or (ii) increasing the myeloid-derived suppressor cells (MDSC) infiltrate or M2-polarized macrophages with greater immunosuppressive functions on NKs and T cells, respectively.

Figure 3

Consequences of indoleamine 2,3 dioxygenase (IDO) overexpression on the antitumoral immune response. Cancer cells frequently overexpress IDO as a result of its transcriptional upregulation. This can be triggered by (i) cytokines such as IFNγ, as long as lymphocytes are present within the tumor, (ii) the oncogene Kit, or (iii) mutations within the tumor suppressor gene Bin. IFNγ promotes IDO overexpression by activating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, while Kit and Bin stimulate ETV4 (ETS variant 4), and STAT1 and/or nuclear factor (NF)-κB, respectively. IDO expression levels can also be regulated by an autocrine loop, implying the complex KYN-AhR. Once in the cytosol, IDO mediates the transformation of tryptophan (TRP) into N-formylkynurenine that is then transformed into kynurenine (KYN). IDO overexpression leads to a decrease in the extracellular level of TRP, which limits the action of immune cells: T cells are not proliferating and can’t be activated; and CD3+ cells infiltrate less frequently and the function of NK cells is reduced. Cells other than cancer cells can overexpress IDO, including some immune cells such as MDSCs and DCs/macrophages. The overexpression of IDO in such cells restrains their own immune function (macrophages), suppresses T cells activity (DCs), and induces protumoral cytokines (MDSCs). As a result, in IDO overexpressing tumors, the antitumoral immune response is largely compromised.

Figure 4

Isocitrate dehydrogenase (IDH) mutations in cancer cells and their clinical impact. Wild-type IDH1 (cytosol) and IDH2/3 (mitochondria) catabolize the oxidative decarboxylation of isocitrate into α-ketoglutarate (α-KG). This reaction generates CO₂ and replenishes NADPH pools in the cell. IDH mutants (IDH^MUT) display a reduced affinity for their natural substrate, while gaining neomorphic activity to convert α-KG into R-2-hydroxyglutarate (R-2-HG). R-2-HG is an oncometabolite that plays a key role in tumor progression. It is usually kept at low levels as it is re-converted into α-KG by dehydrogenases. In IDH mutated cancer cells, these dehydrogenases are overwhelmed by mutant activity, generating very high levels of R-2-HG. R-2-HG principally acts by binding to 2-OG-dependent dioxygenases, such as TET (TET methylcytosine dioxygenase) and Jmj-KDM (Jumonji C domain histone lysine demethylase) proteins. The binding to TET and KDM inhibits activity, increasing DNA and histone methylation patterns, respectively, and, thereby, altering gene expression patterns and cell differentiation. Patients with IDH^MUT tumors seem to respond better to treatment. Moreover, this mutation leads to the expression of a neoantigen that can be a target for vaccinotherapy.

Figure 5

Consequences of hypoxia and HIF-1 production by cancer cells on the immune response. While proliferating, cancer cells develop hypoxic regions at the center of the tumor. This results in HIF-1α stabilization and expression. HIF-1α triggers the expression and release of several cytokines and chemokines that attract monocytes, macrophages and myeloid cells into these regions. In some cancers, monocytes differentiate into TAMs (tumor-associated macrophages) that impair T cell proliferation and cytotoxic properties. In other cases, recruited macrophages trigger inflammation, promoting cancer progression. Some myeloid cells like MDSCs contribute to immunosuppression. Finally, O₂-deprived cancer cells may also produce and release metabolites such as ROS, adenine and lactate that will further block T cell function and increase the recruitment of Tregs with immunosuppressive functions.