Cancer Letters

Cancer Letters

Volume 417, 28 March 2018, Pages 11-20
Cancer Letters

Mini-review
Cancer, obesity and immunometabolism – Connecting the dots

https://doi.org/10.1016/j.canlet.2017.12.019Get rights and content

Highlights

  • Lipid metabolism plays a key role in the tumour microenvironment.

  • Lipid metabolism in both the tumour and immune cells can promote tumour progression.

  • Obesity is associated with impaired immune surveillance.

  • Lipid metabolism may link obesity and increased cancer risk.

Introduction

The immune system plays a vital role in both the prevention and therapy of cancer. Cells of the immune system constantly parole the body for threats and can recognise and kill transformed cells. However, tumours can escape immune surveillance through multiple mechanisms such as immune subversion, downregulation of MHC molecules and acquisition of mutations [1]. Despite many setbacks in the past, recent breakthroughs in cancer immunotherapy with immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapy have highlighted the potential of leukocytes to elicit potent anti-tumour immunity in patients.

Several immune cell types have been implicated in cancer immunosurveillance (Fig. 1). Tumour infiltrating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) can suppress tumour growth, by direct killing of tumour cells or by secretion of pro-inflammatory cytokines which can suppress tumour cell growth and enhance anti-tumour immune responses [2]. Dendritic cells (DCs) are also important for the orchestration of adaptive anti-tumour immune responses, by cross-presenting tumour antigens and activating effector T cell responses [2]. However, the tumour microenvironment (TME) also attracts immunosuppressive immune cells, such as regulatory T (Treg) cells, tumour associated-macrophages (TAMS) and myeloid derived suppressor cells (MDSC), which promote immune evasion and suppress anti-tumour effector cell responses [3]. Moreover, binding of immune checkpoint receptors, such as programmed cell death-1 (PD-1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or T cell immunoreceptor with Ig and ITIM domains (TIGIT), to their respective ligands can suppress effector immune cell function and contribute to T cell exhaustion [4].

Every biological process is supported by intracellular metabolism. In recent years, it has become increasingly evident that immune cell function and exhaustion is strongly affected by, or controlled by, cellular metabolism. Like any cell, immune cells require energy to survive and the availability of nutrients, metabolites and oxygen has profound implications on their activation, differentiation and function [5]. The rapidly changing TME often features a state of metabolic dysfunction and therefore it is not surprising that the composition and architecture of the TME can alter the state of immune cells at the metabolic level [6].

This review will briefly describe the main mechanisms by which the TME affects immunometabolism and anti-tumour immune function; more detailed descriptions have recently been covered in several excellent reviews [[6], [7], [8]]. The focus of this review will be the role of lipid metabolism in tumour and immune cells, which is important in the context of obesity and cancer. There is a strong link between obesity and cancer, with up to 50% of certain cancers being a direct result of obesity [9,10]. Moreover, obesity is predicted to soon overtake smoking as the leading preventable cause of cancer [9,10]. Obesity is associated with metabolic disorder, and systemic metabolic changes likely affect the immune system. We will discuss the effect of obesity and lipid metabolism on cancer cells directly and on anti-tumour immune responses. Moreover, we will discuss possible implications of obesity on cancer immunotherapy which is becoming increasingly important since a significant proportion of cancer patients are overweight or obese.

Section snippets

Glycolysis and immune cell function

Cells can generate energy by multiple mechanisms. Oxidative phosphorylation (OxPhos) produces high amounts of ATP in the mitochondria by oxidizing NADH and FADH2 in the electron transport chain and subsequent phosphorylation of ADP. OxPhos is often the dominant metabolic pathway used by resting/quiescent cells. In contrast, glycolysis does not require oxygen but generates ATP by metabolising glucose. Glycolysis generates less ATP than OxPhos, however, it also generates important building blocks

Lipid metabolism in cancer cells

Lipid metabolism includes the synthesis of lipids for energy stores or to build membranes during cell proliferation, as well as the breakdown of lipids in order to release energy. FAO is the catabolic process by which cells generate energy by oxidisation of fatty acids in the mitochondria. This type of energy generation can dominate when the supply of other nutrients, such as glucose, is limited, and also potentially in a microenvironment where fatty acids dominate, such as the TME [[38], [39],

Obesity-mediated induction of cancer

Obesity has reached epidemic proportions globally, with an estimated 1.9 billion adults (39% of the adult population) being overweight or obese [85]. Obesity threatens to shorten the human lifespan by 5–20 years, the biggest burden being obesity-related diseases, which includes not only type 2 diabetes (T2D) and heart disease but also cancer. Obesity is predicted to overtake smoking as the leading preventable cause of cancer by 2020 [9,10]. Indeed, up to 50% of certain cancer types have been

Effect of obesity on cancer immunotherapy

Immunotherapy for cancer is showing unprecedented success in developing safe and effective treatment for cancer patients using the immune system. Cancer immunotherapy is at the forefront of cancer therapy and immune checkpoint inhibitors have replaced standard care for several cancers in the USA, including melanoma and NSCLC [4]. With a significant proportion of the population being overweight or obese, the effect of obesity on cancer immunotherapy needs to be explored. At the time of writing,

Concluding remarks

Obesity and cancer are linked in many ways. Obesity is a major risk factor for cancer and alters immune responses against cancer, which will have a major impact on cancer immunosurveillance and immunotherapy. Immunometabolism plays a key role in this interaction. Both obesity and the TME have been shown to alter the cellular metabolism of immune cells which can impair immune effector function. Moreover, consequences of obesity such as dysbiosis or T2D diabetes can contribute to the onset of

Conflicts of interest

The authors have no conflict of interest.

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