Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo

Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo

Bibliographic Details
Main Author: Relation, Theresa
Language:English
Published: The Ohio State University / OhioLINK 2018
Subjects:
Neurosciences
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1520289247008425
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1520289247008425
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Neurosciences
spellingShingle Neurosciences
Relation, Theresa
Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
author Relation, Theresa
author_facet Relation, Theresa
author_sort Relation, Theresa
title Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
title_short Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
title_full Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
title_fullStr Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
title_full_unstemmed Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo
title_sort intratumoral delivery of interferon gamma-secreting mscs repolarizes tumor-associated macrophages and suppresses neuroblastoma proliferation in vivo
publisher The Ohio State University / OhioLINK
publishDate 2018
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1520289247008425
work_keys_str_mv AT relationtheresa intratumoraldeliveryofinterferongammasecretingmscsrepolarizestumorassociatedmacrophagesandsuppressesneuroblastomaproliferationinvivo
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15202892470084252021-08-03T07:05:31Z Intratumoral Delivery of Interferon gamma-secreting MSCs Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo Relation, Theresa Neurosciences The immune system is essential to protect the body against both foreign and self-antigens, but dysregulation is one of the major factors in cancer growth and progression. Without the cooperative function of the innate and adaptive immune systems, anti-neoplastic functions are lost. With this in mind, current research has focused on tools to re-harness the immune system to control tumor growth and prevent recurrence. This work contributes to this goal through an investigation of immune modulation in cancer.In the first component of this work, immunomodulation is achieved via combination treatment of bortezomib, oncolytic virus, and NK cell therapy. We investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy. Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)–expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. Combination treatment with bortezomib and oHSV induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIP1 kinase and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy. This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy in glioblastoma patients.In the second portion of the work, immunomodulation is investigated through the use of transgenic cell therapy for neuroblastoma. The standard of care for neuroblastoma, the most common extracranial solid tumor in childhood, consists of surgical resection, chemotherapy, and radiotherapy. While low-risk patients often achieve long-term survival, high-risk patients will frequently relapse with aggressive, therapy-resistant tumors. Moreover, we currently lack established, effective therapies for these patients; hence, long term survival remains below 50 percent. One promising treatment strategy is the delivery of anti-tumor therapeutic agents via cell therapy. Mesenchymal stromal cell (MSC) therapy has been safely utilized to treat diseases such as osteogenesis imperfecta, cardiovascular diseases, osteoarthritis, autoimmune diseases, and cancer. For solid tumors, the pro-inflammatory cytokine interferon-gamma (IFN-gamma) has been shown to decrease tumor proliferation by altering the tumor microenvironment (TME), which supports and protects tumor cells through physical and cellular barriers to cancer-targeting therapy. However, clinical trials have failed to demonstrate efficacy of systemic IFN-gamma therapy due to the high blood concentration required and associated systemic toxicities.Here, we developed an intra-adrenal model of neuroblastoma, characterized by liver and lung metastases. We then engineered MSCs to deliver IFN-gamma directly to the TME. In vitro, these MSCs polarized murine macrophages to the M1 phenotype. In vivo, we attained a therapeutically active TME concentration of IFN-gamma without increased systemic concentration or toxicity. The TME-specific IFN-gamma reduced tumor growth rate and increased survival in two models of T cell deficient athymic nude mice. Absence of this benefit in NSG immunodeficient mouse model indicates a mechanism dependent of the innate immune system. IL-17 and IL-23p19, both uniquely M1 polarization markers, transiently increased in the tumor interstitial fluid. Finally, the MSC vehicle did not promote tumor growth. These findings reveal that MSCs can deliver effective cytokine therapy directly to the tumor while avoiding systemic toxicity. This method transiently induces inflammatory M1 macrophage polarization, which reduces tumor burden in our novel neuroblastoma murine model.Given the known safety profile of IFN-gamma and MSC, this work has the potential to rapidly translate into clinical trials and represents a promising new alternative to systemic cytokine delivery for the treatment of solid tumors. 2018-08-10 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1520289247008425 http://rave.ohiolink.edu/etdc/view?acc_num=osu1520289247008425 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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