Investigating the Influence of Metabolic Syndrome on Cancer Immunotherapy

Abstract

Cancer is a significant cause of morbidity in New Zealand, with breast and colorectal cancers being amongst the most commonly diagnosed. Therapeutic research has moved into immunotherapies, harnessing the immune system to target tumours. One approach uses virus-like particles (VLP) to activate the immune system against specific antigens found on tumour cells. This has been successful in normal weight murine models of breast and colorectal cancer.

Obesity is a highly prevalent disease and contributes to the development of many cancers and may impact the efficacy of treatment. Uric acid is known to be highly immunogenic and chronic hyperuricemia (elevated serum urate) is likely to influence the immune system.

The project aimed to test a known efficacious VLP therapy combined with anti-programmed death ligand (PD-L)1, against models of breast and colorectal cancer in obese and hyperuricemic mice. Mice were grafted with either breast or colorectal cancer and treated with an empty vehicle, VLP alone, or VLP + anti-PD-L1. Tumours were either immunohistochemically stained or T-cells were stained for markers of exhaustion. Populations of immune cells were also determined in the blood.

Slight increases in survival were observed in obese and hyperuricemic mice with breast cancer treated with VLP, although these mouse strains had reduced survival compared to lean mice when treated with VLP + anti-PD-L1. Obese and hyperuricemic mice had reduced levels of tumour-infiltrating lymphocyte (TIL) infiltrate compared to lean mice. TILs tended to have a greater phenotype associated with exhaustion in obese mice.

In colorectal cancer, survival rates increased in obese mice in both treatment groups. Obese mice had similar levels of TIL infiltration to lean mice, which was reduced in hyperuricemic mice. Treatment with VLP increased TIL frequency in obese and hyperuricemic mice but not in lean mice. There were no differences in TIL exhaustion in lean and obese mice. Obese mice had higher counts of circulating neutrophils and inflammatory monocytes in the blood, but had reduced lymphoid-derived dendritic cell and B-cell counts compared to lean mice.

This data suggests that obese and hyperuricemic mice may have reduced responses to immunotherapy, however this varies based on cancer type. Reduced TIL infiltration and increased T-cell exhaustion seen in the breast cancer model may play a role in this.

To examine the effect of obesity on cancer treatment in patients, data from stage I and II colorectal cancer patients were analysed for obesity metrics, muscle mass, and blood parameters to compare survival in designated subpopulations.

Analysing data about visceral fat showed that obese females had the lowest rate of survival, with non-obese females and all males having similar survival levels. Conversely, measuring waist circumference showed that non-obese females had lower rates of survival than obese females, while obese males had lower rates than non-obese males. Patients with low muscle mass tended to have higher survival compared to those with normal muscle mass. Obesity resulted in higher levels of lymphocytes and albumin, but lower levels of neutrophils and platelets. Sarcopenic patients had decreased levels of lymphocytes.

Using visceral fat as a measurement of obesity gives different survival rates compared with standard measures. This may be useful clinically when considering body composition during prognosis. Future research will investigate the effect of body composition on the survival of stage III and IV colorectal cancer patients and may facilitate the development of more personalised and effective treatment regimens.