Harnessing Immune Cells in the Bowel to Fight Cancer

‍By Marina Yakou MRSV
RSV Young Scientist Research Prizes 2023(Biomedical & Health Sciences) - 2nd Place‍

Bowel cancer claims the lives of over 15,500 Australians each year, ranking as the second leading cause of cancer-related deaths in Victoria and the whole country.¹  

The risk of developing bowel cancer rises sharply from age 50, but the number of diagnosed younger Australians has been increasing steadily, and 1 in 15 Australians will develop the disease in their lifetime.²  We therefore need innovative approaches for bowel cancer treatment.

Immunotherapy has emerged as a beacon of hope. This cutting-edge approach involves enhancing the immune system's capacity to identify and eliminate cancer cells. As part of their normal function, immune cells detect and destroy abnormal cells - like cancer cells to prevent or slow cancer growth. But cancer cells have ways to avoid destruction by displaying proteins on their surface that turn off immune cells, having genetic changes that make them less visible to the immune system, or interfering with how the immune system responds to these cancer cells in other ways. Immunotherapy helps the immune system overcome these hurdles to better fight cancer.

However, the current reality is that fewer than 10% of bowel cancer patients respond positively to existing immunotherapies. This limitation underscores the critical need for groundbreaking research to unlock the full potential of immunotherapy in the fight against bowel cancer.

A part of my PhD research, I explored the gut microbiome, a complex ecosystem within the large bowel consisting of trillions of bacteria, viruses, and fungi. This diverse microbial community plays a pivotal role in modulating the immune system. Everyone has a different profile of microbial species in their bowels, and the microbes that are present determine the education that immune cells receive and regulate the immune system. Within this intricate web, gamma delta T cells, a vital group of immune cells in the large bowel, emerged as key players in preventing bowel cancer.³

Gamma delta T cells act as frontline defenders in the bowel. In the Mucosal Immunity and Cancer Lab at the Olivia Newton-John Cancer Research Institute, we found that the abundance and diversity of a person’s microbiome increased the number of gamma delta T cells. When we analysed bowel cancer patient samples, we found that when more gamma delta T cells were present in the tumours, the patients had better outcomes.

The gut microbiome also influenced the ability of gamma delta T cells to fight the cancer. The microbiome strongly influenced gamma delta T cells’ expression of a molecule called TCF-1, and we found that TCF-1 suppressed the natural immune response that gamma delta T cells can normally exert against bowel cancer. Furthermore, when we genetically deleted TCF-1 from gamma delta T cells, there was a significant reduction in the size of tumours.

By targeting gamma delta T cells and their TCF-1 expression, we may be able to develop targeted combination immunotherapies to treat bowel cancer patients more effectively. This newfound understanding of the intricate interplay between the microbiome and immune cells in the large bowel could open new avenues for intervention in the battle against bowel cancer.

References:

1. Cancer Council Victoria. (2021, June). Bowel Cancer. cancervic.org.au/cancer-information/types-of-cancer/bowel_cancer/bowel-cancer.html
2. Bowel Cancer Australia. (2023). What is bowel cancer? bowelcanceraustralia.org/what-is-bowel-cancer#diagnosis
3. Yakou, M., Ghilas, S., Tran, K., et al. (2023). TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Science Immunology, 8(88).  doi.org/10.1126/sciimmunol.adf2163

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