The influence of diet on anti-cancer immune responsiveness

2018
Laura Soldati,corresponding author Laura Di Renzo, Emilio Jirillo, Paolo A. Ascierto, Francesco M. Marincola, and Antonino De Lorenzo

Abstract

Immunotherapy has matured into standard treatment for several cancers, but much remains to be done to extend the reach of its effectiveness particularly to cancers that are resistant within each indication. This review proposes that nutrition can affect and potentially enhance the immune response against cancer.

The general mechanisms that link nutritional principles to immune function and may influence the effectiveness of anticancer immunotherapy are examined. This represents also the premise for a research project aimed at identifying the best diet for immunotherapy enhancement against tumours (D.I.E.T project).

Particular attention is turned to the gut microbiota and the impact of its composition on the immune system. Also, the dietary patterns effecting immune function are discussed including the value of adhering to a healthy diets such as the Mediterranean, Veg, Japanese, or a Microbiota-regulating diet, the very low ketogenic diet, which have been demonstrated to lower the risk of developing several cancers and reduce the mortality associated with them.

Finally, supplements, as omega-3 and polyphenols, are discussed as potential approaches that could benefit healthy dietary and lifestyle habits in the context of immunotherapy.

The link between immunity and nutrition

Food represents not only a source of nutrients for body growth and for the maintenance of essential functions, but also includes dietary components that behave as antigens. Especially, innate and adaptive intestinal immune cells scattered throughout the lamina propria or present within secondary lymphoid organs, such as Peyer’s patches and colonic lymphoid follicles, can elicit a robust response when stimulated by food antigens.

In fact, it has been demonstrated that food ingestion leads to a condition of post-prandial low-grade inflammation, which is not only regional but also systemic [8].

In healthy volunteers serum levels of the inflammatory cytokine, interleukin (IL)-17, dramatically increases 1 h after the ingestion of a western-type hyper caloric breakfast [9]. This was not observed in a control group of individuals who ingested along with breakfast polyphenols containing fruit juice. These substances are characterized by a remarkable anti-inflammatory activity, which accounts for the reduction of IL-17 serum concentration.

A trial conducted in normal weight children, who followed a Mediterranean diet (MD) for 1 year compared to age matched controls, who disregarded health food recommendations, demonstrated different immune profiles [10, 11]. Quite interestingly, at the end of the trial in the former group, salivary levels of the anti-inflammatory cytokine, IL-10, increased, while levels of IL-17 decreased. In the latter group of children, who mostly ate “junk food”, a dramatic increase in IL-17 was observed at the expense of IL-10. In this context, IL-10 is a cytokine predominantly produced by FOXP3+ T regulatory (TREG) cells, which are induced in the intestine by several dietary components, such as vitamins (A and D), polyunsaturated fatty acids (omega-3) and polyphenols.

The homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken in different clinical settings. Overall, obesity, a diet-related disease, represents a systemic inflammatory condition characterized by an excessive production of IL-17 and IL-21, which, in turn, are strong inducers of Th17 cells [12, 13]. The intense and prolonged inflammatory status in obese people is responsible for diabetes, cardiovascular events, neuro-degeneration, and, in some cases, cancer.

Immunosenescence is known as the decline of the immune system with age accounting for increased frequency of infectious, autoimmune and neoplastic diseases in elderly [14]. Hypo-nutrition in aging aggravates the already impaired immunity, since aged people are frequently malnourished in relation to poor socio-economic conditions, mental illnesses and tooth loss [15]. Importantly, lack of proteins and oligo-elements in elderly determines severe immune deficit, which can be fatal. For instance, zinc deficit in elderly is very common, but undiagnosed, thus leading to T cell malfunction and increased frequency of respiratory infections and poor responses to vaccination [16]. Consequently, zinc supplementation in the elderly with zinc deficiency is very effective for the treatment of chronic diseases [17]. Among other natural products, evidence suggests that administration of red grape polyphenols to aged people restores impaired T cell functions, thus increasing protection against winter infections [18]. Moreover, prebiotics, probiotics and symbiotics have been shown to restore innate and adaptive immunity in elderly, also correcting alterations of intestinal microbiota which, under normal conditions, contributes to immune homeostasis, balancing the equilibrium between TREG cells and Th17 cells [19]. The immunomodulation exerted by natural products in elderly is illustrated in Table 1.

Conclusions

The current review highlights the various processes in which nutrient intake could modulate directly or indirectly the immune system and/or the growth of cancer.

Most of the discussion is based on human observation rather than experimental animal models, as the focus of this review was predominantly based on epidemiological grounds. But several experimental models not discussed here extensively substantiate the conclusions.

Yet a gap of knowledge is clear. While the potential mechanisms that may affect immune function and consequently cancer growth and responsiveness to immunotherapy agents have been discovered, very little is known about how they may affect and modulate therapies since parameters linking dietary habits to clinical outcome during immunotherapy are not routinely included.

Here we propose that in the future, detailed information about diet, nutritional status and gut microbiota should be considered in correlative studies during immunotherapy trials identifying parameters that may be relevant to outcome by studying either systemic effects of diet of circulating immune cells, or those that may affect directly the cancer microenvironment. A project is on going to identify the best diets for immunotherapy enhancement against tumours (D.I.E.T project).