Metabolic barriers to cancer immunotherapy

Abstract

Several non-redundant features of the tumour microenvironment facilitate immunosuppression and limit anticancer immune responses. These include physical barriers to immune infiltration, the recruitment of suppressive immune cells and the upregulation of ligands on tumour cells that bind to inhibitory receptors on immune cells. Recent insights into the importance of the metabolic restrictions imposed by the tumour microenvironment on antitumour T cells have begun to inform immunotherapeutic anticancer strategies. Therapeutics that target metabolic restrictions, such as low glucose levels, a low pH, hypoxia and the generation of suppressive metabolites, have shown promise as combination therapies for different types of cancer. In this Review, we discuss the metabolic aspects of the antitumour T cell response in the context of immune checkpoint blockade, adoptive cell therapy and treatment with oncolytic viruses, and discuss emerging combination strategies.

Fig. 1 |. Metabolic barriers acting on different phases of immunotherapeutic response.

Different classes of immunotherapy act on the immune response at different stages of cell differentiation and activation. This is dependent on the mechanism of action of the drug as well as the location of the immune cells. The metabolic requirements and barriers experienced by the adaptive immune response to each treatment differ by location and treatment intervention. This figure highlights the mechanism of action and metabolic barriers to treatment, both in the periphery and in the tumour microenvironment (TME), for each type of immunotherapy covered in this Review. αKG, α-ketoglutarate; CAR, chimeric antigen receptor; DC, dendritic cell; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; T_reg cell, regulatory T cell.

Fig. 2 |. Metabolic suppression in the tumour microenvironment.

The tumour microenvironment imparts metabolic stress on effector CD4⁺ T cells and CD8⁺ T cells through a variety of mechanisms. The rapid proliferation of tumour cells is supported by high rates of glycolysis, which leads to the local depletion of oxygen and glucose levels, resulting in hypoxic regions that contain high levels of lactate. Dysregulated vasculature, a result of increased tumour proliferation, results in damaged and leaky vessels, which reduce blood flow. This reduces oxygen and nutrient levels in the tumour core and prevents metabolites that suppress CD8⁺ T cells from being transported out of the tumour. Suppressive myeloid cells such as myeloid-derived suppressor cells (MDSCs) as well as regulatory T cells (T_reg cells) are abundant within the tumour, and their distinct metabolic profiles allow them to thrive on tumour-derived metabolites. Furthermore, MDSCs, tumour-associated macrophages (TAMs) and T_reg cells produce suppressive metabolites such as adenosine and kynurenine. Adenosine is produced from ATP by the ectoenzymes CD73 and CD39, which are expressed on the surface of these suppressive cells. MDSCs and TAMs produce arginase 1, which utilizes arginine, and indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan into suppressive kynurenine, and reduce the availability of these amino acids within the tumour. These mechanisms starve the T cells in the tumour microenvironment of amino acids. T_reg cells exert their immunosuppressive effects through the expression of inhibitory molecules such as CTLA4 and LAG3, as well as by secreting immunosuppressive cytokines such as IL-10, TGFβ and IL-35. CD8⁺ T cells enter the tumour as PD1⁻ or PD1^low cells with intact mitochondria. Continuous T cell receptor stimulation and hypoxia induce exhaustion in tumour-specific CD8⁺ T cells, characterized by the co-expression of multiple inhibitory receptors (TIM3, LAG3, PD1, TIGIT and so on) and by the loss of functional mitochondria. As a result of the suppressive tumour microenvironment, the most terminally exhausted T cells (PD1^hi T cells) can no longer control tumour growth. Although PD1^low progenitor T cells can be reinvigorated by checkpoint blockade, terminally exhausted PD1^hi T cells cannot, highlighting the need to understand how these cells may be additionally modulated to enhance response to PD1 blockade.