Melanoma is a highly malignant neoplasia with high rates of metastasis in humans and dogs. Regardless of being considered a highly immunogenic neoplasm, the function of the immune system is hampered by the expression of immune checkpoint molecules by the cancer cells. In contrast, soft tissue sarcomas are poorly immunogenic, as Tumor infiltrating Lymphocytes are lacking, or when present they are usually at the periphery of the tumor. Still, soft tissue sarcomas are considered immunosuppressed. Checkpoint molecules from the PD-axis are overexpressed in numerous human malignant neoplasia and have recently gained attention with a few reports in canine tumors. Immunotherapies against these checkpoint molecules have shown great efficacy in humans, but in order to determine translational approaches into canine patients, more research is needed. Here we determined the gene expression of Programed Death receptor-1, and its ligands PD-L1 and PD-L2 in canine tumors with two distinct immune profiles. Our results show that regardless of their immune profiles, melanoma versus soft tissue sarcoma, checkpoint molecules expression was higher in malignant tumors with a higher grade. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal ultrasound focused therapy that induces mechanical stress to the cells, leading to liquefactive necrosis. Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of CD3+ T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasia, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia. / Doctor of Philosophy / Melanoma is a highly malignant tumor and very resistant to therapy for humans and dogs. At the same time, this neoplasia is usually highly infiltrated by cells from the immune system. However, this immune infiltration is often inhibited by molecules expressed by the melanoma cells. In contrast, soft tissue sarcoma is considered poorly immunogenic, as they often contain low levels of immune cell infiltrates but are still considered immune suppressed. In this study, we determined the expression of molecules that inhibit the effect of T lymphocytes, specifically Programed cell death receptor-1, PD-Ligand 1, and PD-Ligand 2 for these neoplasms with distinct immune profiles. We encounter that despite their immune profiles, the expression of these molecules is higher in malignant tumors. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal focused ultrasound therapy that induces mechanical stress to the cancerigenous cells, leading to its death (necrosis). Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasms, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/113575 |
| Date | 30 January 2023 |
| Creators | Stevenson Salinas, Valentina Beatriz |
| Contributors | Biomedical and Veterinary Sciences, LeRoith, Tanya, Huckle, William R., Klahn, Shawna L., Coutermarsh-Ott, Sheryl, Tuohy, Joanne L. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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