Impact of Immunometabolism on Cancer Metastasis: A Focus on T Cells and Macrophages

Abstract

Despite improved treatment options, cancer remains the leading cause of morbidity and mortality worldwide, with 90% of this mortality correlated to the development of metastasis. Since metastasis has such an impact on treatment success, disease outcome, and global health, it is important to understand the different steps and factors playing key roles in this process, how these factors relate to immune cell function and how we can target metabolic processes at different steps of metastasis in order to improve cancer treatment and patient prognosis. Recent insights in immunometabolism direct to promising therapeutic targets for cancer treatment, however, the specific contribution of metabolism on antitumor immunity in different metastatic niches warrant further investigation. Here, we provide an overview of what is so far known in the field of immunometabolism at different steps of the metastatic cascade, and what may represent the next steps forward. Focusing on metabolic checkpoints in order to translate these findings from in vitro and mouse studies to the clinic has the potential to revolutionize cancer immunotherapy and greatly improve patient prognosis.

Figure 1.

T cell metabolic pathways in the different steps of the metastatic cascade. (A) T cell metabolism in the TME. Elevated arginase levels in the TME lead to the inhibition of CD8⁺ T cell response. Tryptophan depletion, in part due to excess IDO production, in the TME also leads to compromised CD8⁺ T cell effector functions. Furthermore, tryptophan metabolism leads to elevated levels of kynurenine further inhibiting effector CD8⁺ T cells. Inhibition of the ACAT1 enzyme, affects cholesterol esterification and results in enhanced CD8⁺ T cell effector function. HIF-1α is known to reduce Treg differentiation through proteosomal degradation of Foxp3. HIF-1α is also associated with mTORC1 activation, increased glycolysis, and Treg decline. TSC1 is a negative regulator of mTORC1 and therefore important for Treg differentiation. Activation of AMPK is crucial for the shift in metabolism from glycolysis to fatty acid oxidation (FAO), therefore, favoring Treg differentiation. Glycolysis leads to excess lactate production, which is toxic for T_E cells and favors Treg cell polarization. AMPK and PD-1 activation lead to CPT1A activation which is a key enzyme in FAO (B) T cell metabolism and the premetastatic niche. Priming the PMN with 27HC has been shown to indirectly lead to reduced numbers of CD8⁺ T cells at metastatic sites. Inhibition of CYP27A1 enzyme targeting 27HC synthesis has been linked to reduced metastasis. Stat3 expression on myeloid cells in the PMN leads to inhibition of CD8⁺ T cells. Expression of STAT3 on myeloid cells in the lymph node PMN results in the inhibition of CD8⁺ T cells. (C) Immunometabolism and metastasis initiation. To the best of our knowledge, there are no metabolism specific factors known. (D) Immunometabolism and cancer cell in circulation. High levels of the arginase enzyme secreted by circulating cancer cells has been shown to inhibit CD8⁺ T cells. (E) Metastatic niche. Prolyl hydroxylase domain (PHD) proteins expressed by T cells suppresses the activity of T_E cells and promotes Treg cells thereby promoting metastasis in the lung. Deletion of Spns2 in mice leads to reduced metastasis to the lung and increased T_E cell numbers.

Figure 2.

Tumor-associated macrophage (TAM) metabolic pathways in the different steps of the metastatic cascade. (A) TAM metabolism in the TME. TAMs polarization occurs as a plethora of states with both anti- and protumoral features, and with different metabolic phenotypes. TAMs are known to support cancer in the early stages by displaying a glycolysis-related inflammatory function, followed by a switch to a more oxidative phosphorylation (OXPHOS) related function in the later stages of tumor progression. The switch to glycolysis in TAMs is under the control of the Akt–mTOR–HIF-1–PKM2 axis. The sustained glycolysis enhances lactic acid accumulation in the TME, which leads to the acquisition of a protumoral function of TAMs. Furthermore, TAMs rely on uptake and oxidation of extracellular lipids, but also express high levels of fatty acid synthase (FASN) and PPARγ to favor tumor progression and metastasis. Immunosuppressive and protumoral TME is also sustained by PGE2 and iron release, tryptophan and arginine metabolism. Glutamine metabolism is another crucial pathway, indeed, the activity of glutamine synthetase (GS) in TAMs promotes the immune escape, angiogenesis, and metastatic dissemination. (B) TAM metabolism and the premetastatic niche. To the best of our knowledge, there are no information about metabolic remodeling in TAMs. (C) Immunometabolism and metastasis initiation. In a tumor context, in which glutamine tissue levels are not homogeneous, due to the presence of cells with different glutaminolytic capacity, TAMs sense glutamine deprivation and induce GS, which metabolically reprograms TAMs toward a proangiogenic and prometastatic phenotype. In a hypoxic TME, macrophagic arginine metabolism leads to nitric oxide (NO) production, which promotes tumor blood vessel normalization and endothelial cell (EC) activation. Furthermore, REDD1 up-regulation in hypoxic TAMs, which inhibits mTOR, lowers TAM glucose consumption and thus favors ECs glycolytic hyperactivation and dysfunctional blood vessel formation, which ultimately leads to metastasis initiation. (D) Immunometabolism and cancer cell in circulation. Knowledge about the metabolic crosstalk between CTC and macrophages is scarce. (E) Metastatic niche. NADPH oxidase (NOX) 1 and 2 deficiency impair the macrophagic protumoral function during tumor development, leading to decreased metastasis. Furthermore, the macrophages at the metastatic niche might influence the availability of specific nutrients: this is the case of REDD1 up-regulation in hypoxic conditions and GS up-regulation in response to extracellular glutamine deprivation.