Therapeutically remodelling the immune profile of ‘cold’ tumours in obesity associated cancer

Dr. Melissa Conroy, Caroline Marion and Joyce Barry

Dr. Melissa Conroy is an assistant professor in the department of Anatomy at Trinity College Dublin. She was awarded with 5 For The Fight Research Fellowship in partnership with Breakthrough Cancer Research. Caroline Marion is a PhD student working with Dr. Conroy on this project since 2022.  In 2024, Dr. Conroy added to her group Joyce Barry starting as a PhD student.

People with cancer of the food-pipe (oesophageal cancer) receive treatments that only work for 30% of people. Therefore, approximately 70% of people with oesophageal cancer will not benefit from chemo-radiotherapy and urgently need new treatments. Our immune system is designed to kill cancer cells, but in people who have cancer the immune system is weakened.

Natural killer (NK) cells destroy cancer cells. However, in obese oesophageal cancer patients, NK cells are pulled into the visceral fat by a protein called fractalkine. Once in the fat, NK cells are profoundly altered and die before they can reach the tumour.

In oesophageal tumours, the highest obesity levels are linked to the lowest numbers of NK cells. We know a drug called a CX3CR1 antagonist targets the action of fractalkine and can block fractalkine from pulling NK cells into the fat.

Now Dr. Conroy and her team of researchers will test whether this drug can free NK cells from the fat so that they could move towards and kill oesophageal cancer cells. Through their research, we’ll also learn if NK cell therapies can be changed to bypass the fat and boost tumour destruction in oesophageal cancer.

Ultimately, we’ll learn if two new immunotherapies can improve survival in oesophageal cancer.

RESEARCH FINDINGS

Publications

Lysaght J, Conroy MJ. The multifactorial effect of obesity on the effectiveness and outcomes of cancer therapies. Nat Rev Endocrinol. 2024 Dec;20(12):701-714. doi: 10.1038/s41574-024-01032-5. Epub 2024 Sep 23. PMID: 39313571.

Mylod E, O’Connell F, Donlon NE, Davern M, Marion C, Butler C, Reynolds JV, Lysaght J, Conroy MJ. Real-time ex vivo monitoring of NK cell migration toward obesity-associated oesophageal adenocarcinoma following modulation of CX3CR1. Sci Rep. 2024 Feb 18;14(1):4017. doi: 10.1038/s41598-024-54390-5. PMID: 38369570; PMCID: PMC10874956.

Davern, M.; O’ Donovan, C.; Donlon, N.E.; Mylod, E.; Gaughan, C.; Bhardwaj, A.; Sheppard, A.D.; Bracken-Clarke, D.; Butler, C.; Ravi, N.; Lysaght, J., Conroy, M.J. Analysing the Combined Effects of Radiotherapy and Chemokine Receptor 5 Antagonism: Complementary Approaches to Promote T Cell Function and Migration in Oesophageal Adenocarcinoma. Biomedicines 2024, 12, 819. https://doi.org/10.3390/biomedicines12040819

Mylod E, McKenna E, Davern M, Barr MP, Donlon NE, Bibby BAS, Bhardwaj A, Reynolds JV, Lysaght J, Maher SG, Conroy MJ. Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses. Clin Exp Med. 2023 Jun;23(2):411-425. doi: 10.1007/s10238-022-00811-6. Epub 2022 Apr 1. PMID: 35364779; PMCID: PMC10224847.

Conference Presentations

Irish Society of Immunology Annual Meeting 2022, Maynooth University, Ireland. Title: “Elucidating the pro-tumourigenic effects of fractalkine in oesophageal adenocarcinoma” – Presented by: Caroline Marion.

12th International Cancer Conference 2022, St.James’s hospital, Dublin, Ireland. Title”Investigating the role of fractalkine in oesophageal adenocarcinoma tumour growth and epithelial-mesenchymal transition” – Presented by: Caroline Marion..

Irish Association for Cancer Research Conference (IARC) 2023, Dublin, Ireland. Title: “Investigating the anti-proliferative and anti-metastatic potential of CX3CR1 antagonism in oesophageal adenocarcinoma” – Presented by: Caroline Marion.

Chemotactic cytokines – Gordon Research Conference 2024, Portland, USA. Title: “Modulation of the chemokine receptor CXCR1 with E6130 ameliorates the pro-tumourigenic
effects of fractalkine in oesophageal adenocarcinoma” – Presented by: Caroline Marion.

European Conference of Immunology 2024, Dublin Ireland. Title: “Fractalkine: a chemokine with protumourigenic effects in oesophageal adenocarcinoma that can be attenuated by CX3CR1 modulation with E6130” – Presented by: Caroline Marion. Title: “‘Investigating the applicability of KHYG-1 cell therapy for obesity associated cancer” – Presented by: Joyce Barry.

EACR-AACR-IACR, Basic and Translational Research Conference 2024, Dublin, Ireland. Title: “‘CX3CR1 modulation can attenuate fractalkine-induced pro-tumourigenic effects in oesophageal adenocarcinoma” – Presented by: Caroline Marion.

46th ESPEN Congress Clinical Nutrition & Metabolism 2024, Milan, Italy. Title: “Obesity: implications for cancer treatment” – Presented by: Dr. Melissa Conroy

Awards

HSE Open Access Research Award (Integrated Services Category) 2024. Awardee: Dr. Melissa Conroy

TSJCI Crest Award 2024 (€12,000.00, PI): Elucidating the potential of combination Olaparib and Natural Killer cell therapy in non-small lung cancer. Awardee: Dr. Melissa Conroy

Immunotools Special Award 2024. Awardee: Caroline Marion