Understanding the role of gamma delta (γδ) T cells in pancreatic cancer metastasis

Lawrence, Mark (2022) Understanding the role of gamma delta (γδ) T cells in pancreatic cancer metastasis. PhD thesis, University of Glasgow.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 1-year survival rate of 5.6% and a 10-year survival rate of <1%. In Scotland, 3 in 5 people with pancreatic cancer are diagnosed at late-stage metastatic disease, and surgical resection remains the only effective cure for patients with nonmetastatic disease. Given late-stage diagnosis and low rates of surgical resection, understanding the mechanisms of metastatic disease is of the utmost importance. In breast cancer, IL-17A+ gamma delta (γδ) T cells are potently prometastatic and drive myeloid cell expansion which impairs anti-metastatic CD8+ T cells. In PDAC, IL-17A has been implicated in early-stage PDAC progression, and γδ T cells have been shown to be abundant in human PDAC. Therefore, I sought to understand the role of γδ T cells in PDAC metastasis, and if they can promote metastasis in a similar manner as seen in breast cancer.

Using spontaneous KrasG12D;Trp53R172H;Pdx1-Cre (KPC) mice, I have phenotyped γδ T cells in mouse PDAC and assessed their role in PDAC tumourigenesis and metastasis. In short, IL-17A+ γδ T cells are significantly infiltrated into PDAC tumours, and Vγ6+ γδ T cells (considered IL-17A-producers) are expanded in KPC spleen. Crucially, the absence of γδ T cells in KPC mice leads to a two-fold reduction in the incidence of spontaneous liver metastasis. Contrasting with breast cancer, γδ T cells do not mediate crosstalk with neutrophils by systemic cytokine production, but instead communicate locally with tumour-associated macrophages within the PDAC TME. Furthermore, γδ T cells promote the expansion of the embryonic-derived (tissue-resident) macrophage compartment, which have greater pro-tumour function than monocyte-derived macrophages.

These results reveal that tumour-infiltrated γδ T cells in PDAC display a protumour phenotype, and that γδ T cells are indispensable for metastatic dissemination. They also reveal a novel phenotype where γδ T cells mediate crosstalk with macrophages specifically within the primary PDAC tumour. Further work is required to understand the mechanism of this crosstalk, but these findings may have important implications for the identification of future targets of anti-metastatic therapies.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Coffelt, Dr. Seth
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-82705
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Feb 2022 14:43
• Last Modified: 08 Apr 2022 16:50
• Thesis DOI: 10.5525/gla.thesis.82705
• URI: https://theses.gla.ac.uk/id/eprint/82705