Checkpoint inhibitor immunotherapy is promising, however still requires an improvement in response and development of markers to predict the patients who would benefit from this therapy.
Neutrophils are abundant blood cell population and known to play anti- or pro-tumour roles depending on the context.
Expressed in the neutrophils, a chemokine receptor CXCR2 plays an essential role in their recruitment to inflammatory cites, and its inhibition has been shown to suppress tumorigenesis and metastasis in various cancer types.
Furthermore, studies in the pancreatic cancer model have shown that Cxcr2 inhibition resulted in a reduction of pro-tumour neutrophils in tumours, allowing T cells to repopulate, thereby sensitizing them to the checkpoint inhibitor.
In the bladder, an increased expression of CXCR2 ligands is reported to be associated with tumour progression and poor prognosis, however the roles of tumour infiltrating neutrophils remain largely undefined.
In order for neutrophils to be targeted in bladder cancer, it is essential to obtain a better understanding of neutrophil biology in the bladder, in comparisons to other tumour types.
The project asks the following questions:
-What are the roles of tumour-infiltrating neutrophils in tumour progression in the bladder?
-What are the characteristics of immune phenotype of neutrophil-enriched tumours, and how do they related to the disease progression?
In the project, we will explore the neutrophil-enriched tumour microenvironment by characterizing the topography of immune cell populations and gene expressions in mouse and human tumour tissues.
The objectives are:
(1) to establish methodologies in multiplex immunohistochemistry (mIHC) followed by the quantitative pathology imaging (QPI) and evaluate the validity of artificial intelligence (AI) / machine learning-based analytical processes in digital pathology platforms
(2) to characterise the relationships between tumour infiltrating lymphocytes and Cxcr2+ myeloid cells by topographical analysis
(3) to identify the critical factors leading to the above immune phenotype by gene expression profiling and analysis at the tissue level.
The overall goal of this study is to understand the roles of neutrophils in bladder cancer progression, and to evaluate the potential of neutrophils or CXCR2 as a new target of immunotherapy.
Through this project, the student is expected to gain a significant expertise in tissue-based research based on hands-on experiences in a variety of cutting-edge histopathology technologies, quantitative digital pathology image analysis, immune and gene profiling, management of tissue resources and large-scale data based on model and clinical specimens.
1. Powles, T., Immune Checkpoint Inhibitors for Urologic Cancer: The Tip of the Iceberg? Eur Urol, 2015. 68(2): p. 280-2.
2. Coffelt, S.B., M.D. Wellenstein, and K.E. de Visser, Neutrophils in cancer: neutral no more. Nat Rev Cancer, 2016. 16(7): p. 431-46.
3. Jamieson, T., et al., Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J Clin Invest, 2012. 122(9): p. 3127-44.
4. Steele, C.W., et al., CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell, 2016. 29(6): p. 832-845.
5. Foth, M., et al., Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice. J Pathol, 2014. 233(2): p. 148-58.
6. Foth, M., et al., FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. J Pathol, 2018. 246(3): p. 331-343.
7. Gartrell, R.D., et al., Quantitative Analysis of Immune Infiltrates in Primary Melanoma. Cancer Immunol Res, 2018. 6(4): p. 481-493.
Open for self-funded students with funding in place to cover bench fees, tuition fees and living costs for the duration of the PhD project.
How good is research at University of Glasgow in Clinical Medicine?
FTE Category A staff submitted: 177.40
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