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Understanding gamma delta T cells in colon cancer metastasis

Periodic Reporting for period 1 - GDCOLCA (Understanding gamma delta T cells in colon cancer metastasis)

Okres sprawozdawczy: 2018-06-01 do 2020-05-31

Colon cancer is a leading cause of death worldwide and over 370,000 new cases are diagnosed each year in countries of the European Union. Early-stage colon cancer is curable but there is no effective therapy for metastatic disease. Strikingly, less than 10% of patients with Stage IV metastatic disease live beyond 5 years. As such, the development of an effective therapy for metastatic cancer is desired. For this, understanding the mechanisms of metastasis is essential.
So far, much of the work in metastasis biology has focused on how cancer cells develop and acquire a metastatic phenotype. However, the role of the immune system during the metastatic process has received far less attention and is largely unknown. Immune cells can both promote and prevent metastasis. Immune cells have been shown to participate in each step of the metastatic cascade, including formation of the pre-metastatic environment. Recent studies have provided new insights about two particular types of immune cells, called neutrophils and gamma/delta T cells. Also, IL-17, an important pro-tumour cytokine produced from gamma/delta T cells, links neutrophils and gamma/delta T cells. Recently, a novel molecule called BTNL1 has been reported as a critical activator of intestine specific gamma/delta T cells. The role of BTNL1 has not previously been investigated in any cancer models.
The gamma/delta T cells-IL-17-neutrophil axis was recently shown by my host institute supervisor to promote breast cancer metastasis. However, the significance of this axis in other cancers’ metastasis remains unaddressed. In this action, my objectives were to : 1. clarify characteristics of gamma/delta T cells in colorectal cancer metastasis, 2. assess if depletion of gamma/delta T cells by a neutralizing antibody as well as crossing the mouse colorectal cancer metastasis model with gamma/delta T cell-deficient mice would reduce the occurrence of metastasis, and 3. examine the involvement of BTNL1, which is a specific activator for anti-tumorigenic IFN-producing gamma/delta T cells in the intestine. So, my goal was to understand the role of these gamma/delta T cells in colon cancer development and metastasis.
I have achieved most of the objectives during the action period. I have revealed the characteristics of gamma/delta T cells in colorectal cancer metastasis. I have assessed the requirement of gamma/delta T cells in colorectal cancer metastasis and neutrophil expansion. I have also examined role of BTNL1 molecule in colorectal cancer development. The involvement of BTNL1 in colorectal cancer metastasis has not been addressed and I am still working on this aspect. These achievements clarified the significance of gamma/delta T cells in colorectal cancer development and metastasis and identified potential targets for immunotherapy that may help patients with metastatic colon cancer in future.
I have generated a genetically engineered mouse model of colorectal cancer metastasis. To characterise the features of gamma/delta T cells in the mouse colorectal cancer metastasis model, I performed flow cytometry analysis on immune cells from the blood, lymph node, liver, small intestine and tumour. I revealed that these cells in the tumour are IL-17 positive, less activated and l have a less cytotoxic phenotype. I have generated a mouse model of colorectal cancer metastasis with lack of gamma/delta T cells. Also, I performed tumour organoid transplantation into the colons of gamma/delta T cell deficient mice to examine the effect of gamma/delta T cell loss in tumour growth. Using those models, I performed flow cytometry analysis to examine the number of neutrophils. The results showed that gamma/delta T cells promote tumour growth and neutrophil expansion. I have generated two other mouse cancer models without gamma/delta T cells. These two models develop only the primary tumours but not metastasis and these models are used to examine the role of BTNL1 in cancer development. I showed that BTNL1 does not affect tumour development. Taken together, these results suggest that gamma/delta T cells but not the intestine specific type of gamma/delta T cells control neutrophils in a mouse colorectal cancer model. Targeting gamma/delta T cells would be more beneficial than targeting neutrophils because gamma/delta T cells act upstream of neutrophil expansion. Also, neutrophil turnover is so quick (about 8 hours in humans) that clinical application would need frequent injection of depleting antibodies, while turnover of gamma/delta T cells is slow (turnover of T cells is months to years in humans). Those findings are still based on a mouse model, so my next step will be to determine whether this is the same in humans before clinical application.
To disseminate these findings, I have attended the National Cancer Research Institute Conference (November, 2018) and utilised this chance to network and exchange ideas with the speakers. I have also had opportunities to present my data at the ACRCelerate workshop (November, 2019), the Institute of Infection, Immunity & Inflammation seminar presentation (January 2019), the Edinburgh-Glasgow Joint Cancer Immunology Meeting (October 2018), 2 host Institute-internal seminars. Through this dissemination, I obtained new ideas and many suggestions from the audiences.
It was previously unknown that gamma/delta T cells are involved in colorectal cancer metastasis. I was able to characterise BTNL1 to see if it and its target intestine specific subtype of gamma/delta T cells could be a potential new therapy for colorectal cancer.
The schematic of our findings and hypothesis