Fibrinogen-like protein 2 (FGL2) expression is associated with tumour progression and poor survival in a number of different cancers. In these cancers, FGL2 promotes tumour progression via an immunosuppression-mediated mechanism or by promoting angiogenesis. Querying single-cell RNA sequencing (scRNA-seq) human cancer data shows FGL2 is produced by immune and stromal cells in the tumour microenvironment (TME), while cancer cells have minimal expression of FGL2. We therefore studied the role of FGL2 produced by cells in the TME in tumour progression in two models of cancer in which the role of FGL2 has not been previously studied: epithelial ovarian cancer (EOC) and melanoma.
EOC is the most lethal gynecologic cancer with an imperative need for new treatments. Before testing novel immunotherapies, we first characterized the TME of six syngeneic ovarian cancer models. ID8-p53-/- and ID8-C3 tumours were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumours were primarily infiltrated by tumour associated macrophages and were unique in MHC class I and II expression. This panel of well-defined murine EOC models can serve as a valuable resource for studies that aim to test immunotherapies.
We next studied the role of FGL2 in tumour progression in melanoma and ovarian cancer models. Using wild-type and FGL2 knockout mice, we found that absence of FGL2 led to a more activated TME, including activated dendritic cells (DCs - CD86+, CD40+) and T cells (CD25+, TIGIT+), as well as demonstrating for the first time that the absence of FGL2 led to more activated Natural Killer (NK) cells (DNAM-1, NKG2D) in the TME. The absence of FGL2 prolonged survival in the B16F10 model of melanoma, and synergized with oncolytic virus to prolong survival in the ID8-p53-/-Brca2-/- model of ovarian cancer.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/44333 |
| Date | 02 December 2022 |
| Creators | Galpin, Kristianne |
| Contributors | Vanderhyden, Barbara |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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