Investigating the Effects of Chronic Low-Grade Inflammation on Cancer Immunotherapy

Abstract

Cancer is the leading cause of death in New Zealand and is responsible for approximately one third of all deaths. Due to various factors, including unhealthy life style choices and an aging population, the number of new cases is expected to rise by close to 70% over the next 20 years. While current cancer treatments are effective in most cases, in aggressive cases they are rarely curative, and their lack of specificity can lead to many unwanted side effects. These limitations have propelled research toward more targeted therapies, including immune system harnessing therapies such as cancer immunotherapies. Cancer immunotherapies, including cancer vaccines, such as virus-like particle (VLP) vaccines, have demonstrated effective improvements in disease-free survival in mouse models of melanoma, colorectal and breast cancer. However, such therapies have not been tested under conditions where the immune system is altered, as seen in chronic inflammation. With many conditions that have underlying chronic low-grade inflammation, such as metabolic disorders, on the rise, this may be an important aspect of cancer treatment to consider. In light of this, the aim of this project was to investigate the effect of chronic low-grade inflammation on the ability of VLP-peptide vaccines to induce anti-tumour immunity against melanoma, colorectal and breast cancer.

To investigate this, hyperuricemic and obese mouse strains as chronic inflammatory models were used. A pilot tumour growth kinetics study was conducted to assess differences in tumour growth rates in our inflamed mouse models. To assess differences in adaptive immune cell activation in response to the vaccines in vivo, mice were vaccinated, and antibody production and T cell cytotoxicity were evaluated. Lastly, bone marrow (BM) cells and BM derived dendritic cells (BMDCs) from wild type, hyperuricemic and obese murine models were analysed by flow cytometry, along with co-cultured T cells, to identify markers associated with activation, proliferative potential and effector function.

In vivo experiments revealed that breast cancer tumour growth decreased, and overall survival increased in the hyperuricemic and possibly the obese mice compared to the wild type mice, however no differences were seen in the other models. No difference was observed between the melanoma vaccine-induced cytotoxicity in the hyperuricemic mice compared to the wild type mice. However, lower antibody titres were detected in the blood of hyperuricemic mice in response to the breast and colorectal cancer vaccine as compared with the wild type mice. Analysis of immune cell populations in the BM did not reveal any differences between the frequencies of dendritic cells (DCs), B and T cells from the three mice models. However, the BM cells from the obese mice showed increased frequencies of myeloid and immunosuppressive cells. DCs from the BM of obese mice had decreased MHC class II (MHC II) expression when unstimulated and decreased activation marker expression following CpG stimulation. Lastly, DCs from the three mice models were all able to stimulate T cell proliferation following VLP stimulation, a trend indicates that DCs from the obese mice BM were able to generate the greatest level of proliferation.

In conclusion, this data suggests that the reduced breast cancer tumour growth rate in hyperuricemic mice may be due to the increased interleukin-10 (IL-10) in these animals. Additionally, the higher frequency of myeloid and immunosuppressive cells in the BM of obese mice and the decreased expression of activation markers and MHC II on DCs from obese mice may affect anti-tumour immunity downstream.

Future experiments will determine the impact of an altered immune system, as a result of chronic low-grade inflammation, in the obese and hyperuricemic mice on our VLP-peptide vaccine’s ability to generate an anti-tumour response against melanoma, colorectal and breast cancer.