{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/125911"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/125911","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"E3 Ubiquitin Ligase Cbl-b deficient T cells resist Treg cell-mediated suppression and enhance anti-tumor immunity","abstract":"Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity.","abstract_html":"Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity.","abstract_has_math":false,"creators":["Han, Seong Jun"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Immunology","school":null,"contributors":[],"advisors":["Ohashi, Pamela S"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-11","date_published":"2021-11","updated_at":"2026-07-27T21:28:05Z","subjects":["Cancer immunology","Immuno-oncology","Immunotherapy","Regulatory T cell","T cell"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/125911","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Ohashi, Pamela S"]},{"key":"dc:contributor.department","label":"Department","values":["Immunology"]},{"key":"dc:creator","label":"Author","values":["Han, Seong Jun"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2021-11"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2022-11-29T05:12:11Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2022-11-29T05:12:11Z"]},{"key":"dc:date.issued","label":"Date","values":["2021-11"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Cancer immunology","Immuno-oncology","Immunotherapy","Regulatory T cell","T cell"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/125911"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["E3 Ubiquitin Ligase Cbl-b deficient T cells resist Treg cell-mediated suppression and enhance anti-tumor immunity"]}]}],"canonical_facts":{"dc:contributor.advisor":["Ohashi, Pamela S"],"dc:contributor.department":["Immunology"],"dc:creator":["Han, Seong Jun"],"dc:date":["2021-11"],"dc:date.accessioned":["2022-11-29T05:12:11Z"],"dc:date.available":["2022-11-29T05:12:11Z"],"dc:date.issued":["2021-11"],"dc:description.abstract":["Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1807/125911"],"dc:subject":["Cancer immunology","Immuno-oncology","Immunotherapy","Regulatory T cell","T cell"],"dc:title":["E3 Ubiquitin Ligase Cbl-b deficient T cells resist Treg cell-mediated suppression and enhance anti-tumor immunity"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:05Z"}