Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy.

Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future.

Obesity is a major risk factor for developing cancer, with obesity-induced immune changes and inflammation in breast (BC) and colorectal cancer (CRC) providing a potential link between the two. This study investigates systemic effects of obesity on adaptive and innate immune cells in healthy and tumour-bearing mice. Immune cells from lean and obese mice were phenotyped prior to implantation of either BC (C57mg and EO771.LMB) or CRC (MC38) cells as tumour models. Tumour growth rate, tumour-infiltrating lymphocytes (TIL) and peripheral blood immune cell populations were compared between obese and lean mice. In vitro studies showed that naïve obese mice had higher levels of myeloid cells in the bone marrow and bone marrow-derived dendritic cells expressed lower levels of activation markers compared to cells from their lean counterparts. In the tumour setting, BC tumours grew faster in obese mice than in lean mice and lower numbers of TILs as well as higher frequency of exhausted T cells were observed. Data from peripheral blood showed lower levels of myeloid cells in tumour-bearing obese mice. This study highlights that systemic changes to the immune system are relevant for tumour burden and provides a potential mechanism behind the effects of obesity on cancer development and progression in patients.

The gastrointestinal (GI) tumour microenvironment is characterised by its unique colonisation with bacteria that are estimated to match the total number of cells in our body. It is becoming increasingly clear that the microbiome and its metabolites are important orchestrators of local and systemic immune responses, anticancer immunity and the host response to cancer therapy. Apart from their role as an energy source, metabolites have been shown to modulate inflammation, immune cell function and cancer cell survival. The polarisation of immune cell subsets by microbial metabolites towards either pro- or antitumorigenic functions strongly affects cancer progression and outcomes. In this chapter, we will discuss the link between microbial metabolites in the GI tumour microenvironment, anticancer immune responses and cancer progression.