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PD-L1 Expression by Tumor Macrophages: Regulation and Signaling
Başlık:
PD-L1 Expression by Tumor Macrophages: Regulation and Signaling
Yazar:
Hartley, Genevieve, author.
ISBN:
9780438042476
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (144 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Steven Dow Committee members: Barbara Biller; Mercedes Gonzalez-Juarrero; Alan Schenkel.
Özet:
Immune checkpoint molecules maintain self-tolerance and prevent uncontrolled inflammation. However, expression of these molecules is often dysregulated in the tumor microenvironment (TME), resulting in overexpression of inhibitory checkpoint molecules such as programmed cell death ligand 1 (PD-L1). This overexpression suppresses T cell activation and effector functions, which interferes with T cell control of tumors. PD-1 and its ligand PD-L1 are inhibitory checkpoint molecules that suppress tumor immunity, and PD-L1 also binds CD80 to inhibit T cell responses. The field of tumor immunotherapy has established that interrupting the PD-1/PD-L1 signaling pathway with therapeutic antibodies can potently activate T cell responses to tumors. For example, PD-L1 antibody treatment increases T cell infiltration and IFN-gamma production, and decreases tumor growth in mouse models. Blockade of either molecule with specific antibodies has now been shown to induce dramatic anti-tumor responses in patients with many tumor types. Importantly, relatively few adverse effects were observed in these trials.
The excitement generated by these developments in the treatment of human cancers has been dampened by the realization that only a small subset of patients respond to immunotherapy. This has prompted numerous studies attempting to identify biomarkers that can predict response to treatment and has also illuminated the need for animal models that more accurately translate human biology and disease progression. Countless therapies developed in rodents have failed to successfully treat human disease, but pet dogs with spontaneously-occurring disease are emerging as a promising model for many reasons. These include strong similarities in anatomy and physiology between dogs and humans, as well as vast differences in genetics, living environment, and diet between dogs that parallel variations found between human patients. Furthermore, advances in the care of animals has allowed for longer lifespans for pet dogs, which has led to an increase in the incidence of many age-related diseases such as cancer. Therefore, the field of comparative oncology utilizes the knowledge gained by treating veterinary patients with spontaneously-occurring disease to improve our understanding of human disease while also translating therapies used for human care to veterinary patients.
Very little is known concerning the expression and regulation of canine immune checkpoint molecules in either normal tissues or by tumors. Therefore, in the studies described in Chapter 2, we measured the expression of PD-L1 by a panel of canine tumor cell lines and by primary canine macrophages and further assessed the effects of immune stimuli on PD-L1 expression by these cells. These studies showed PD-L1 to be constitutively expressed by all 14 canine tumor cell lines evaluated, and PD-L1 expression was upregulated upon stimulation by IFN-gamma and a TLR3 ligand. In contrast, canine macrophages did not express PD-L1 under basal conditions but expression was induced upon treatment with IFN-gamma. These results are consistent with those reported in humans and in mice, where PD-L1 is primarily regulated by IFN-gamma produced by activated T cells. In tumors, this is a mechanism of tumor-mediated T cell suppression that is an important target of immunotherapy, and this study suggests that PD-1 and PD-L1 blockade may be beneficial for the treatment of canine tumors.
Lymphoma is one of most commonly diagnosed cancers in dogs, but to-date there has been little progress in improving prognosis. Protocols for the treatment of canine lymphoma were adapted from those used to treat human patients because chemotherapeutic agents are similarly effective between the two patient groups, and at the same time, drugs that are ineffective in humans are also ineffective for dogs. PD-1-targeted immunotherapy has been found to be highly effective in the treatment of human lymphoma, and thus canine lymphoma may be a disease that benefits from this therapy. Therefore, we characterized the PD-1 and PD-L1 expression profile in canine lymphoma and the effects of chemotherapy resistance on these expression levels, which is detailed in Chapter 3. We first analyzed PD-1 and PD-L1 expression using fine needle aspirates of lymph nodes from healthy dogs and from dogs with untreated B cell lymphoma (BCL) and T cell lymphoma (TCL). We found increased expression of PD-L1 by BCL compared to healthy B cells, but low to negative expression of PD-1 and PD-L1 by both healthy and malignant T cells. Next, we generated chemotherapy-resistant BCL and TCL cell lines and compared their expression of PD-1 and PD-L1 to untreated cells. (Abstract shortened by ProQuest.).
Notlar:
School code: 0053
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678895.1) | 678895-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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