How we can target the underlying immune processes in pathological inflammation in obesity, cancer and liver disease.
Dr. Melissa Conroy, TTMI
I am an immunologist and senior research fellow in the Cancer Immunology and Immunotherapy Group, Department of Surgery at Trinity College Dublin. My research is focused on developing novel immunotherapies in the space of obesity, cancer and liver disease with a specific focus on lymphocyte trafficking and chemokine networks.
My research examines how we can target the underlying immune processes in pathological inflammation in obesity, cancer and liver disease. My PhD was focused on immune responses to chronic hepatitis virus infection and identified novel functions of natural killer cells and innate T cells in viral hepatitis. More recently, my research focus has shifted to pathologies associated with the burgeoning global health burden of obesity, primarily investigating immunological mechanisms underlying non-alcoholic fatty liver disease (NAFLD) and cancer. Another strand of my research assesses how immunotherapeutics might augment anti-tumour immune responses in upper gastrointestinal cancer and examines the safety of such therapeutics in inflammation-driven cancer. Specifically, my studies address how chemokine pathways might be manipulated to enhance anti-tumour immunity and alleviate pathological inflammation in obesity. Such studies are conducted in collaboration with industry partners and international scientists.
Tumour burden and cancer patient outcomes are heavily affected by the level of immune cell infiltration in the primary tumour. Immune cell movement is controlled by a network known as the chemokine system that provides a roadmap and directs immune cells to sites of infection, wounds and malignancy in the body. Novel treatments that enhance T cell responses such as checkpoint inhibitors and CAR T cells are showing great promise and such targeted immunotherapies are expected to revolutionize cancer treatment. My work is focused on identifying and assessing novel immunotherapies with a specific focus on those that can boost immune cell infiltration of tumours in patients with obesity-associated and inflammation-driven malignancy.
The worldwide obesity epidemic has been described as a global catastrophe in slow motion, with no country successfully curbing its escalation and prevalence tripling since 1975. The World Health Organisation estimates that 1.9 billion adults and 41 million children worldwide are overweight or obese and at great risk of developing obesity-associated disease such as diabetes, cancer or heart disease. Therefore, my research examines novel ways to treat and prevent these diseases, particularly the obesity-associated cancer oesophageal adenocarcinoma. Oesophageal adenocarcinoma (OAC) is an aggressive malignancy, with a dismal five year survival rate of only ~18%, mainly due to a poor treatment response rate of ~30%. Of all malignancies, OAC has one of the strongest associations with obesity and is one of the deadliest cancers placing it as one of the top 5 leading causes of cancer-related deaths in males aged between 40 and 59. Worryingly, incidence rates have increased 38% in Ireland alone since the 1990s, with predicted increases of up to 160% in males by 2040. Therefore, novel treatments are urgently required to improve outcomes for the increasing number of patients with OAC, both nationally and globally.
My recent published work has shown that T cells required for tumour eradication are recruited to the inflamed sites of visceral adipose tissue (VAT) and liver in OAC patients and we have identified the chemokine pathways responsible for this recruitment. The movement of T cells toward the VAT and liver away from the tumour poses a huge problem for launching effective anti-tumour immune responses. Moreover, such compromised T cell infiltration of the tumour could also potentially reduce the efficacy of immunotherapies. Therefore, my current studies aim to redirect T cells to the tumour. Recently, we have demonstrated effective blockade of T cell trafficking to the VAT and liver of OAC patients using novel chemokine receptor antagonists targeting CCR1. Targeting the CCR1 pathway not only gives the T cells a chance to traffic to the tumour but also offers a dual benefit of reducing VAT inflammation through reduction of inflammatory T cell infiltration to the VAT. Therefore, this approach may also have prophylactic utility in obese individuals at high risk of diseases caused by chronic and pathological obesity-associated inflammation, most notably non-alcoholic fatty liver disease. I am currently testing the efficacy of CCR1 antagonists in vivo.
In other areas of my research, I am examining the potential safety implications of checkpoint inhibitors in obesity-associated cancer. Patients with obesity-associated malignancies such as OAC are chronically inflamed and we have already reported that the tissues of the VAT and liver are enriched with inflammatory T cells in this patient cohort. Since checkpoint inhibitors function to enhance T cell activities, my latest research assesses whether such immunotherapies exacerbate the existing body wide inflammation in patients with obesity-associated cancer. The data generated from this study could have implications on the consideration and management of checkpoint inhibitors for malignancies that arise in a background if obesity and/or inflammation.
My overall research objectives are to improve upon current treatment regimens by developing more targeted and effective treatments for patients with OAC. This would in turn facilitate augmented treatment response and survival rates among patients who currently face a paucity of treatment options. Furthermore, the therapeutic approaches currently under investigation may also have implications for other obesity-associated malignancies and further research will elucidate this. Finally, at a time when the worsening obesity epidemic shows no signs of abating, my research examines how we might prevent disease in the growing number of patients at huge risk of developing obesity-associated pathologies.
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