{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/86634"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/86634","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"PGE2 Blockade Enhances the Magnitude and Selectivity of the BCG-Induced Immune Response in the Human Bladder Cancer Microenvironment","abstract":"M.S.","abstract_html":"M.S.","abstract_has_math":false,"creators":["Ibrahim, Omar; 0000-0002-9903-6657"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Kalinski, Pawel","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-02-21T21:35:51Z","date_published":"2025-02-21T21:35:51Z","updated_at":"2026-07-27T19:05:32Z","subjects":["medicine","immunology","therapy"],"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/10477/86634","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kalinski, Pawel","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Ibrahim, Omar; 0000-0002-9903-6657"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-02-21T21:35:51Z","2020"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["medicine","immunology","therapy"]}]},{"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/10477/86634"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["M.S.","Background: Bacillus Calmette-Guérin (BCG) is commonly used in the immunotherapy of non-muscle invasive urothelial cancer (bladder cancer; BlCa), however, its effectiveness is limited. Here, we evaluated the molecular pathways regulating the patterns of BCG-induced inflammation in the BlCa tumor microenvironment (TME) and the feasibility of their therapeutic modulation. Experimental Design: Human monocyte-derived macrophages or human BlCa tissue explants were exposed ex vivo to BCG in the absence or presence of NFkB inhibitors and/or blockers of PGE2 synthesis or signaling. The expression of inflammatory mediators and chemokine genes, secretion of chemokines, and their cellular sources and NFkB translocation were analyzed by quantitative PCR, ELISA, flow cytometry, and confocal microscopy. Chemotaxis of human CTLs and Tregs was evaluated using migration chambers. Results: BCG-exposed macrophages and BlCa explants showed strong induction of MDSC- and Treg-attracting chemokines (CXCL8, CXCL12, and CCL22), which correlated with nuclear translocation of phosphorylated NFkB, the induction of COX2 (the key enzyme controlling PGE2 biosynthesis) and elevation of the PGE2 receptor, EP4. These undesirable effects of BCG were counteracted by blockade of NFkB. Blockade of COX2 activity in BCG-treated macrophages and BlCa explants using COX2 or COX1/2 inhibitors (celecoxib, indomethacin) or interference with PGE2 signaling (using the EP4 blocker, ARY-007) selectively enhanced the production of CTL attractants (CCL5, CXCL9, and CXCL10), but suppressed the induction of MDSC/Treg attractants (CCL22, CXCL8, CXCL12), and immunosuppressive mediators (COX2, IL10, NOS2, and IDO1). Conclusions: Our data demonstrate that the PGE2 antagonism can enhance the magnitude of BCG-driven production of CTL attractants in BlCa tumor explants with concomitant suppression of Treg/MDSC attractants and immuno-suppressive factors. Since CTL accumulation in the TME predict long term outcomes in patients with BlCa and many other cancers and predicts antitumor effects of immunotherapy, our data provide a rationale for targeting the PGE2 system to enhance the therapeutic effects of BCG.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["PGE2 Blockade Enhances the Magnitude and Selectivity of the BCG-Induced Immune Response in the Human Bladder Cancer Microenvironment"]}]}],"canonical_facts":{"dc:contributor":["Kalinski, Pawel","Roswell Park"],"dc:creator":["Ibrahim, Omar; 0000-0002-9903-6657"],"dc:date":["2025-02-21T21:35:51Z","2020"],"dc:description":["M.S.","Background: Bacillus Calmette-Guérin (BCG) is commonly used in the immunotherapy of non-muscle invasive urothelial cancer (bladder cancer; BlCa), however, its effectiveness is limited. Here, we evaluated the molecular pathways regulating the patterns of BCG-induced inflammation in the BlCa tumor microenvironment (TME) and the feasibility of their therapeutic modulation. Experimental Design: Human monocyte-derived macrophages or human BlCa tissue explants were exposed ex vivo to BCG in the absence or presence of NFkB inhibitors and/or blockers of PGE2 synthesis or signaling. The expression of inflammatory mediators and chemokine genes, secretion of chemokines, and their cellular sources and NFkB translocation were analyzed by quantitative PCR, ELISA, flow cytometry, and confocal microscopy. Chemotaxis of human CTLs and Tregs was evaluated using migration chambers. Results: BCG-exposed macrophages and BlCa explants showed strong induction of MDSC- and Treg-attracting chemokines (CXCL8, CXCL12, and CCL22), which correlated with nuclear translocation of phosphorylated NFkB, the induction of COX2 (the key enzyme controlling PGE2 biosynthesis) and elevation of the PGE2 receptor, EP4. These undesirable effects of BCG were counteracted by blockade of NFkB. Blockade of COX2 activity in BCG-treated macrophages and BlCa explants using COX2 or COX1/2 inhibitors (celecoxib, indomethacin) or interference with PGE2 signaling (using the EP4 blocker, ARY-007) selectively enhanced the production of CTL attractants (CCL5, CXCL9, and CXCL10), but suppressed the induction of MDSC/Treg attractants (CCL22, CXCL8, CXCL12), and immunosuppressive mediators (COX2, IL10, NOS2, and IDO1). Conclusions: Our data demonstrate that the PGE2 antagonism can enhance the magnitude of BCG-driven production of CTL attractants in BlCa tumor explants with concomitant suppression of Treg/MDSC attractants and immuno-suppressive factors. Since CTL accumulation in the TME predict long term outcomes in patients with BlCa and many other cancers and predicts antitumor effects of immunotherapy, our data provide a rationale for targeting the PGE2 system to enhance the therapeutic effects of BCG.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/86634"],"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":["medicine","immunology","therapy"],"dc:title":["PGE2 Blockade Enhances the Magnitude and Selectivity of the BCG-Induced Immune Response in the Human Bladder Cancer Microenvironment"],"dc:type":["Text","Thesis"]},"updated_at":"2026-07-27T19:05:32Z"}