{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/79418"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/79418","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Interferon Regulatory Factor 8 (IRF8) Transcriptionally Regulates the Macrophage Response During Tumor Immunosurveillance","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Twum, Danielle"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Abrams, Scott","Immunology"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-04-04T20:32:42Z","date_published":"2019-04-04T20:32:42Z","updated_at":"2026-07-27T19:05:16Z","subjects":["biology","molecular"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/79418","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Abrams, Scott","Immunology"]},{"key":"dc:creator","label":"Author","values":["Twum, Danielle"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-04-04T20:32:42Z","2019","2019-01-17 12:01:43"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["biology","molecular"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/79418"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","The macrophage response in neoplasia is governed by transcriptional pathways thought to be regulated by stromal or tumor-derived soluble factors bathing the tumor microenvironment. In neoplasia high infiltration of macrophages is associated with reduced overall survival as well as progression to metastasis. This is because in neoplasia macrophages are shunted toward a more tumor and metastasis promoting phenotype. Although several transcriptional regulators that drive the tumor and metastasis-promoting phenotype in macrophages have been identified, transcription factors that drive or enforce an anti-tumor or anti-metastatic phenotype are not as well defined. IRF8 (Interferon Regulatory Factor-8) is a transcriptional regulator of multiple aspects of myeloid biology, including differentiation and functional status. In the case of function, it is well-known that IRF8 is critical for the expression of genes such as iNOS and IL-12p40, hallmark features of an M1 phenotype, which is characterized as an anti-tumor phenotype. However, the role of IRF8 in macrophage-tumor biology is unknown. Based on this rationale, we hypothesize that the presence of IRF8 in macrophages plays an important role in their ability to control primary tumor and/or progression to metastasis, especially as tumor-associated macrophages have been linked to disease progression in many cancers. To test this hypothesis, we utilized an IRF8 knockout model (IRF8fl/fl) whereby IRF8 is specifically deleted in the macrophage compartment (LysM-Cre) and compared the rate of tumor growth as well as propensity for lung metastasis. Reduced IRF8 expression in macrophages resulted in increased lung metastasis in orthotopic implantable models of mouse mammary cancer and melanoma. This reduced expression of IRF8 in macrophages lent itself to a gene signature that was pro-metastatic. An IRF8 signature in macrophages was also an indicator of overall survival in breast, melanoma and lung cancer patients where an increased IRF8 expression correlated with a higher overall survival. We also explored the concept of macrophage reeducation and reprogramming by utilizing an in vitro culture system. In this setting, macrophages were exposed to opposing signals and we identified a repolarization network in macrophages with IRF8 as an axis. Altogether, these data indicate that IRF8 expression in macrophages can impact tumor progression to metastasis, likely through altering the tumor-suppressing vs. tumor-promoting phenotypes. Thus, IRF8 may represent a potentially novel therapeutic target to modulate the macrophage phenotype in neoplastic settings, such as mammary cancer, whereby this myeloid response is a critical determinant of outcome."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Interferon Regulatory Factor 8 (IRF8) Transcriptionally Regulates the Macrophage Response During Tumor Immunosurveillance"]}]}],"canonical_facts":{"dc:contributor":["Abrams, Scott","Immunology"],"dc:creator":["Twum, Danielle"],"dc:date":["2019-04-04T20:32:42Z","2019","2019-01-17 12:01:43"],"dc:description":["Ph.D.","The macrophage response in neoplasia is governed by transcriptional pathways thought to be regulated by stromal or tumor-derived soluble factors bathing the tumor microenvironment. In neoplasia high infiltration of macrophages is associated with reduced overall survival as well as progression to metastasis. This is because in neoplasia macrophages are shunted toward a more tumor and metastasis promoting phenotype. Although several transcriptional regulators that drive the tumor and metastasis-promoting phenotype in macrophages have been identified, transcription factors that drive or enforce an anti-tumor or anti-metastatic phenotype are not as well defined. IRF8 (Interferon Regulatory Factor-8) is a transcriptional regulator of multiple aspects of myeloid biology, including differentiation and functional status. In the case of function, it is well-known that IRF8 is critical for the expression of genes such as iNOS and IL-12p40, hallmark features of an M1 phenotype, which is characterized as an anti-tumor phenotype. However, the role of IRF8 in macrophage-tumor biology is unknown. Based on this rationale, we hypothesize that the presence of IRF8 in macrophages plays an important role in their ability to control primary tumor and/or progression to metastasis, especially as tumor-associated macrophages have been linked to disease progression in many cancers. To test this hypothesis, we utilized an IRF8 knockout model (IRF8fl/fl) whereby IRF8 is specifically deleted in the macrophage compartment (LysM-Cre) and compared the rate of tumor growth as well as propensity for lung metastasis. Reduced IRF8 expression in macrophages resulted in increased lung metastasis in orthotopic implantable models of mouse mammary cancer and melanoma. This reduced expression of IRF8 in macrophages lent itself to a gene signature that was pro-metastatic. An IRF8 signature in macrophages was also an indicator of overall survival in breast, melanoma and lung cancer patients where an increased IRF8 expression correlated with a higher overall survival. We also explored the concept of macrophage reeducation and reprogramming by utilizing an in vitro culture system. In this setting, macrophages were exposed to opposing signals and we identified a repolarization network in macrophages with IRF8 as an axis. Altogether, these data indicate that IRF8 expression in macrophages can impact tumor progression to metastasis, likely through altering the tumor-suppressing vs. tumor-promoting phenotypes. Thus, IRF8 may represent a potentially novel therapeutic target to modulate the macrophage phenotype in neoplastic settings, such as mammary cancer, whereby this myeloid response is a critical determinant of outcome."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/79418"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["biology","molecular"],"dc:title":["Interferon Regulatory Factor 8 (IRF8) Transcriptionally Regulates the Macrophage Response During Tumor Immunosurveillance"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:16Z"}