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Liver Macrophages in Pancreatic Cancer Metastasis / Stacy K Thomas.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Thomas, Stacy K., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Cellular biology.
- Oncology.
- Therapy.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Local Subjects:
- Immunology.
- Cellular biology.
- Oncology.
- Therapy.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Physical Description:
- 1 online resource (146 pages)
- Contained In:
- Dissertations Abstracts International 84-08A.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2022
- Language Note:
- English
- Summary:
- For patients with pancreatic ductal adenocarcinoma (PDAC), metastatic disease is the main cause of mortality with the liver being the most common site of metastasis. Macrophages are proponents of metastasis and contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth. However, macrophage biology is pliable such that macrophages can be polarized with anti-tumor activity. Thus, macrophage polarization could be an approach for intervening on metastasis. Here, we model liver metastasis with an intraportal (iPo) injection of a LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre;LSL-Rosa26-Yfp (KPCY) cell line. Liver macrophages were depleted using clodronate encapsulated liposomes (CEL) and Kupffer cells (KCs) were depleted in Clec4fDTR mice by administering diphtheria toxin (DT). While in the normal liver macrophages promote metastatic outgrowth, here we show that macrophages respond to treatment with a myeloid agonist, β-glucan, by inhibiting liver metastasis. Transcriptional analysis via single cell RNA sequencing and analysis of surface markers by flow cytometry demonstrated that β-glucan treatment triggered activation of liver resident macrophages (Kupffer cells). Furthermore, immunohistochemistry studies showed that β-glucan treatment suppressed cancer cell proliferation and invoked productive anti-metastatic T cell immunity in our pancreatic cancer mouse models. Although Kupffer cells were excluded from metastatic lesions, studies in Clec4fDTR mice revealed that Kupffer cells were critical for the treatment's anti-metastatic activity, which also required T cells. Moreover, β-glucan treatment remodeled the immune response to liver metastases in mice and humans, resulting in more immunostimulatory macrophages and increased T cell density in metastatic lesions. Further, β-glucan treatment sensitized metastatic lesions to anti-PD1 therapy. Together, these findings demonstrate the significance of macrophage polarity in metastasis and identify Kupffer cells as a novel therapeutic target for invoking T cell immunity against liver metastasis and reversing resistance to anti-PD-1 immunotherapy.
- Notes:
- Source: Dissertations Abstracts International, Volume: 84-08, Section: A.
- Advisors: Beatty, Gregory L.; Committee members: Brodsky, Igor; Bassiri, Hamid; Haldar, Malay; Eisenlohr, Laurence.
- Department: Immunology.
- Ph.D. University of Pennsylvania 2022.
- Local Notes:
- School code: 0175
- ISBN:
- 9798374413069
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
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