{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/28023"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/28023","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"Augmenting Anti-Tumor Immunity by Targeting Macrophage Cox-2 in Breast Cancer","abstract":"Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast. While the contributions of tumor cell-derived COX-2 are well studied, those of the stroma remain ill-defined. Macrophages, an essential component of the tumor microenvironment, exist within a range of two polar phenotypes, influenced by signals in their local environment: anti-tumorigenic M1 or pro-tumorigenic M2. M2-like tumor-associated macrophages (TAM) are positively associated with tumorigenesis. This thesis investigates the contribution of macrophage COX-2 in two models of HER2/neu-induced mammary tumorigenesis utilizing mice selectively lacking macrophage COX-2 (COX-2^MØKO) and the contribution of COX-2 derived products in modifying macrophage phenotype in vitro. Finally, a targeted macrophage COX-2 inhibitor is investigated in vitro and in vivo as a potential cancer therapeutic. Deletion of macrophage COX-2 led to reduced mammary tumorigenesis coincident with fewer TAMs and reduction in M2 characteristics of TAM. Further, depletion of CD8+ cytotoxic T lymphocytes (CTLs), but not CD4+ T helper and regulatory cells, restored tumor growth in COX-2^MØKO mice, suggesting enhanced CTL function caused by reduction in total and M2-like TAM. Investigation of COX-2-mediated polarization of bone marrow-derived macrophages (BMDM) in vitro revealed paracrine influences of prostaglandin (PG) E2 in modifying polarized macrophage phenotype to more closely resemble TAM. Interestingly, interference with macrophage COX-2 did not significantly modify BMDM polarization. This suggested that autocrine COX-2 minimally affects BMDM phenotype, and that polarization of COX-2^MØKO BMDM does not recapitulate reduced M2 characteristics observed in COX-2^MØKO TAM. Reconstituted high-density lipoprotein (rHDL) nanoparticles were utilized as a method to target macrophages in vitro and in vivo. rHDL conjugated to fluorescent dye DiR revealed efficient incorporation of rHDL nanoparticles with TAM. In preliminary experiments utilizing rHDL-celecoxib as a targeted macrophage COX-2 inhibitor, marked suppression of PGD2 and PGE2 generation was evident in lipopolysaccharide (LPS)-stimulated J774A.1 cells. Importantly, urinary prostaglandin levels were not altered in mice treated with rHDL-celecoxib, suggesting no systemic inhibition of COX-2 with this targeted approach. These studies provide rationale for targeting macrophage COX-2 in mammary tumorigenesis and provide essential preliminary experiments in translating these findings into a potential chemopreventative or chemotherapeutic agent.","abstract_html":"Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast. While the contributions of tumor cell-derived COX-2 are well studied, those of the stroma remain ill-defined. Macrophages, an essential component of the tumor microenvironment, exist within a range of two polar phenotypes, influenced by signals in their local environment: anti-tumorigenic M1 or pro-tumorigenic M2. M2-like tumor-associated macrophages (TAM) are positively associated with tumorigenesis. This thesis investigates the contribution of macrophage COX-2 in two models of HER2/neu-induced mammary tumorigenesis utilizing mice selectively lacking macrophage COX-2 (COX-2^MØKO) and the contribution of COX-2 derived products in modifying macrophage phenotype in vitro. Finally, a targeted macrophage COX-2 inhibitor is investigated in vitro and in vivo as a potential cancer therapeutic. Deletion of macrophage COX-2 led to reduced mammary tumorigenesis coincident with fewer TAMs and reduction in M2 characteristics of TAM. Further, depletion of CD8+ cytotoxic T lymphocytes (CTLs), but not CD4+ T helper and regulatory cells, restored tumor growth in COX-2^MØKO mice, suggesting enhanced CTL function caused by reduction in total and M2-like TAM. Investigation of COX-2-mediated polarization of bone marrow-derived macrophages (BMDM) in vitro revealed paracrine influences of prostaglandin (PG) E2 in modifying polarized macrophage phenotype to more closely resemble TAM. Interestingly, interference with macrophage COX-2 did not significantly modify BMDM polarization. This suggested that autocrine COX-2 minimally affects BMDM phenotype, and that polarization of COX-2^MØKO BMDM does not recapitulate reduced M2 characteristics observed in COX-2^MØKO TAM. Reconstituted high-density lipoprotein (rHDL) nanoparticles were utilized as a method to target macrophages in vitro and in vivo. rHDL conjugated to fluorescent dye DiR revealed efficient incorporation of rHDL nanoparticles with TAM. In preliminary experiments utilizing rHDL-celecoxib as a targeted macrophage COX-2 inhibitor, marked suppression of PGD2 and PGE2 generation was evident in lipopolysaccharide (LPS)-stimulated J774A.1 cells. Importantly, urinary prostaglandin levels were not altered in mice treated with rHDL-celecoxib, suggesting no systemic inhibition of COX-2 with this targeted approach. These studies provide rationale for targeting macrophage COX-2 in mammary tumorigenesis and provide essential preliminary experiments in translating these findings into a potential chemopreventative or chemotherapeutic agent.","abstract_has_math":false,"creators":["Chen, Edward Po-Hwa"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Emer M. Smyth"],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-01-01","date_published":"2014-01-01","updated_at":"2026-07-24T03:46:00Z","subjects":[],"languages":["en"],"rights":["Edward Po-Hwa Chen"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/28023","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Emer M. 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While the contributions of tumor cell-derived COX-2 are well studied, those of the stroma remain ill-defined. Macrophages, an essential component of the tumor microenvironment, exist within a range of two polar phenotypes, influenced by signals in their local environment: anti-tumorigenic M1 or pro-tumorigenic M2. M2-like tumor-associated macrophages (TAM) are positively associated with tumorigenesis. This thesis investigates the contribution of macrophage COX-2 in two models of HER2/neu-induced mammary tumorigenesis utilizing mice selectively lacking macrophage COX-2 (COX-2^MØKO) and the contribution of COX-2 derived products in modifying macrophage phenotype in vitro. Finally, a targeted macrophage COX-2 inhibitor is investigated in vitro and in vivo as a potential cancer therapeutic. Deletion of macrophage COX-2 led to reduced mammary tumorigenesis coincident with fewer TAMs and reduction in M2 characteristics of TAM. Further, depletion of CD8+ cytotoxic T lymphocytes (CTLs), but not CD4+ T helper and regulatory cells, restored tumor growth in COX-2^MØKO mice, suggesting enhanced CTL function caused by reduction in total and M2-like TAM. Investigation of COX-2-mediated polarization of bone marrow-derived macrophages (BMDM) in vitro revealed paracrine influences of prostaglandin (PG) E2 in modifying polarized macrophage phenotype to more closely resemble TAM. Interestingly, interference with macrophage COX-2 did not significantly modify BMDM polarization. This suggested that autocrine COX-2 minimally affects BMDM phenotype, and that polarization of COX-2^MØKO BMDM does not recapitulate reduced M2 characteristics observed in COX-2^MØKO TAM. Reconstituted high-density lipoprotein (rHDL) nanoparticles were utilized as a method to target macrophages in vitro and in vivo. rHDL conjugated to fluorescent dye DiR revealed efficient incorporation of rHDL nanoparticles with TAM. In preliminary experiments utilizing rHDL-celecoxib as a targeted macrophage COX-2 inhibitor, marked suppression of PGD2 and PGE2 generation was evident in lipopolysaccharide (LPS)-stimulated J774A.1 cells. Importantly, urinary prostaglandin levels were not altered in mice treated with rHDL-celecoxib, suggesting no systemic inhibition of COX-2 with this targeted approach. These studies provide rationale for targeting macrophage COX-2 in mammary tumorigenesis and provide essential preliminary experiments in translating these findings into a potential chemopreventative or chemotherapeutic agent."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy (PhD)"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Augmenting Anti-Tumor Immunity by Targeting Macrophage Cox-2 in Breast Cancer"]}]}],"canonical_facts":{"dc:contributor.advisor":["Emer M. Smyth"],"dc:creator":["Chen, Edward Po-Hwa"],"dc:date":["2023-05-17T12:45:51.000"],"dc:date.accessioned":["2023-05-22T16:28:10Z"],"dc:date.available":["2014-08-10T00:00:00Z"],"dc:date.issued":["2014-01-01"],"dc:description.abstract":["Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast. While the contributions of tumor cell-derived COX-2 are well studied, those of the stroma remain ill-defined. Macrophages, an essential component of the tumor microenvironment, exist within a range of two polar phenotypes, influenced by signals in their local environment: anti-tumorigenic M1 or pro-tumorigenic M2. M2-like tumor-associated macrophages (TAM) are positively associated with tumorigenesis. This thesis investigates the contribution of macrophage COX-2 in two models of HER2/neu-induced mammary tumorigenesis utilizing mice selectively lacking macrophage COX-2 (COX-2^MØKO) and the contribution of COX-2 derived products in modifying macrophage phenotype in vitro. Finally, a targeted macrophage COX-2 inhibitor is investigated in vitro and in vivo as a potential cancer therapeutic. Deletion of macrophage COX-2 led to reduced mammary tumorigenesis coincident with fewer TAMs and reduction in M2 characteristics of TAM. Further, depletion of CD8+ cytotoxic T lymphocytes (CTLs), but not CD4+ T helper and regulatory cells, restored tumor growth in COX-2^MØKO mice, suggesting enhanced CTL function caused by reduction in total and M2-like TAM. Investigation of COX-2-mediated polarization of bone marrow-derived macrophages (BMDM) in vitro revealed paracrine influences of prostaglandin (PG) E2 in modifying polarized macrophage phenotype to more closely resemble TAM. Interestingly, interference with macrophage COX-2 did not significantly modify BMDM polarization. This suggested that autocrine COX-2 minimally affects BMDM phenotype, and that polarization of COX-2^MØKO BMDM does not recapitulate reduced M2 characteristics observed in COX-2^MØKO TAM. Reconstituted high-density lipoprotein (rHDL) nanoparticles were utilized as a method to target macrophages in vitro and in vivo. rHDL conjugated to fluorescent dye DiR revealed efficient incorporation of rHDL nanoparticles with TAM. In preliminary experiments utilizing rHDL-celecoxib as a targeted macrophage COX-2 inhibitor, marked suppression of PGD2 and PGE2 generation was evident in lipopolysaccharide (LPS)-stimulated J774A.1 cells. Importantly, urinary prostaglandin levels were not altered in mice treated with rHDL-celecoxib, suggesting no systemic inhibition of COX-2 with this targeted approach. These studies provide rationale for targeting macrophage COX-2 in mammary tumorigenesis and provide essential preliminary experiments in translating these findings into a potential chemopreventative or chemotherapeutic agent."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/28023"],"dc:language":["en"],"dc:rights":["Edward Po-Hwa Chen"],"dc:title":["Augmenting Anti-Tumor Immunity by Targeting Macrophage Cox-2 in Breast Cancer"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:46:00Z"}