{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/150065"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/150065","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Dendritic cell dysfunction restrains cytotoxic T cell responses against cancer","abstract":"Although immune checkpoint blockade (ICB) therapy can induce durable survival benefits in patients with advanced cancer, most patients do not respond. ICB acts by reinvigorating pre-existing anti-tumor immune responses, and responders are often characterized by the presence of a T cell infiltrate in tumors. However, T cell infiltration does not always correspond to ICB efficacy. Tumor-reactive T cells can acquire persistent dysfunctional states, which are resistant to ICB reinvigoration. Increasing evidence suggests that T cell dysfunction can arise during T cell priming. Dendritic cells (DCs) play a key role in priming tumor-reactive T cells, indicating that DC-derived signals could regulate the functional quality of anti-tumor T cell responses. In this work, we investigated how cancer-associated suppression of DCs could lead to dysfunctional anti-tumor T cell responses. First, we explored tissue-specific mechanisms that could mediate lung tumor-specific T cell dysfunction, previously found to be induced during T cell priming in the lung tumor-draining lymph node (tdLN). We determined that the T cell dysfunction was caused by regulatory T cell (Treg)-mediated suppression of DC stimulatory capacity. Suppression required direct contact between Tregs and DCs and was specifically associated with the presence of clonally-expanded T helper type 1 (TH1)-like Tregs. TH1-like Tregs were induced in response to elevated levels of interferon-gamma (IFNγ) in the lung tdLN. Administration of IFNγ-blocking antibody could counter the tissue-specific enrichment in IFNγ, repolarize Tregs and restore cytotoxic T cell responses against lung cancer. Next, we examined longitudinal changes in anti-tumor immunity associated with the observed decline in ICB efficacy in later-stages tumors. We found that ICB resistance at later timepoints was accompanied by T cell dysfunction and a decline in stimulatory DCs in both the tumor and tdLN. Treatment with Poly(I:C) could enhance T cell and DC responses at later timepoints, providing a clear rationale for combination immunotherapy using Poly(I:C) and ICB. Our work demonstrates that distinct tissue-specific and temporal elements can suppress DC ability to support productive anti-tumor immunity. Counteracting these mechanisms of DC dysfunction has the potential to enhance cytotoxic T cell responses and help better leverage the potential of anti-tumor immunity for long-term disease control.","abstract_html":"Although immune checkpoint blockade (ICB) therapy can induce durable survival benefits in patients with advanced cancer, most patients do not respond. ICB acts by reinvigorating pre-existing anti-tumor immune responses, and responders are often characterized by the presence of a T cell infiltrate in tumors. However, T cell infiltration does not always correspond to ICB efficacy. Tumor-reactive T cells can acquire persistent dysfunctional states, which are resistant to ICB reinvigoration. Increasing evidence suggests that T cell dysfunction can arise during T cell priming. Dendritic cells (DCs) play a key role in priming tumor-reactive T cells, indicating that DC-derived signals could regulate the functional quality of anti-tumor T cell responses. In this work, we investigated how cancer-associated suppression of DCs could lead to dysfunctional anti-tumor T cell responses. First, we explored tissue-specific mechanisms that could mediate lung tumor-specific T cell dysfunction, previously found to be induced during T cell priming in the lung tumor-draining lymph node (tdLN). We determined that the T cell dysfunction was caused by regulatory T cell (Treg)-mediated suppression of DC stimulatory capacity. Suppression required direct contact between Tregs and DCs and was specifically associated with the presence of clonally-expanded T helper type 1 (TH1)-like Tregs. TH1-like Tregs were induced in response to elevated levels of interferon-gamma (IFNγ) in the lung tdLN. Administration of IFNγ-blocking antibody could counter the tissue-specific enrichment in IFNγ, repolarize Tregs and restore cytotoxic T cell responses against lung cancer. Next, we examined longitudinal changes in anti-tumor immunity associated with the observed decline in ICB efficacy in later-stages tumors. We found that ICB resistance at later timepoints was accompanied by T cell dysfunction and a decline in stimulatory DCs in both the tumor and tdLN. Treatment with Poly(I:C) could enhance T cell and DC responses at later timepoints, providing a clear rationale for combination immunotherapy using Poly(I:C) and ICB. Our work demonstrates that distinct tissue-specific and temporal elements can suppress DC ability to support productive anti-tumor immunity. Counteracting these mechanisms of DC dysfunction has the potential to enhance cytotoxic T cell responses and help better leverage the potential of anti-tumor immunity for long-term disease control.","abstract_has_math":false,"creators":["Zagorulya, Maria"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Biology","school":null,"contributors":[],"advisors":["Spranger, Stefani"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-02","date_published":"2023-02","updated_at":"2026-07-22T22:21:25Z","subjects":[],"languages":[],"rights":["In Copyright - Educational Use Permitted","Copyright MIT"],"rights_urls":["http://rightsstatements.org/page/InC-EDU/1.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1721.1/150065","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Spranger, Stefani"]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Department of Biology"]},{"key":"dc:creator","label":"Author","values":["Zagorulya, Maria"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-03-31T14:29:24Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-03-31T14:29:24Z"]},{"key":"dc:date.issued","label":"Date","values":["2023-02"]},{"key":"dc:publisher","label":"Institution","values":["Massachusetts Institute of Technology"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctoral","Doctor of Philosophy"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["In Copyright - Educational Use Permitted","Copyright MIT"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/page/InC-EDU/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1721.1/150065"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Although immune checkpoint blockade (ICB) therapy can induce durable survival benefits in patients with advanced cancer, most patients do not respond. ICB acts by reinvigorating pre-existing anti-tumor immune responses, and responders are often characterized by the presence of a T cell infiltrate in tumors. However, T cell infiltration does not always correspond to ICB efficacy. Tumor-reactive T cells can acquire persistent dysfunctional states, which are resistant to ICB reinvigoration. Increasing evidence suggests that T cell dysfunction can arise during T cell priming. Dendritic cells (DCs) play a key role in priming tumor-reactive T cells, indicating that DC-derived signals could regulate the functional quality of anti-tumor T cell responses. In this work, we investigated how cancer-associated suppression of DCs could lead to dysfunctional anti-tumor T cell responses. First, we explored tissue-specific mechanisms that could mediate lung tumor-specific T cell dysfunction, previously found to be induced during T cell priming in the lung tumor-draining lymph node (tdLN). We determined that the T cell dysfunction was caused by regulatory T cell (Treg)-mediated suppression of DC stimulatory capacity. Suppression required direct contact between Tregs and DCs and was specifically associated with the presence of clonally-expanded T helper type 1 (TH1)-like Tregs. TH1-like Tregs were induced in response to elevated levels of interferon-gamma (IFNγ) in the lung tdLN. Administration of IFNγ-blocking antibody could counter the tissue-specific enrichment in IFNγ, repolarize Tregs and restore cytotoxic T cell responses against lung cancer. Next, we examined longitudinal changes in anti-tumor immunity associated with the observed decline in ICB efficacy in later-stages tumors. We found that ICB resistance at later timepoints was accompanied by T cell dysfunction and a decline in stimulatory DCs in both the tumor and tdLN. Treatment with Poly(I:C) could enhance T cell and DC responses at later timepoints, providing a clear rationale for combination immunotherapy using Poly(I:C) and ICB. Our work demonstrates that distinct tissue-specific and temporal elements can suppress DC ability to support productive anti-tumor immunity. Counteracting these mechanisms of DC dysfunction has the potential to enhance cytotoxic T cell responses and help better leverage the potential of anti-tumor immunity for long-term disease control."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Dendritic cell dysfunction restrains cytotoxic T cell responses against cancer"]}]}],"canonical_facts":{"dc:contributor.advisor":["Spranger, Stefani"],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Biology"],"dc:creator":["Zagorulya, Maria"],"dc:date.accessioned":["2023-03-31T14:29:24Z"],"dc:date.available":["2023-03-31T14:29:24Z"],"dc:date.issued":["2023-02"],"dc:description.abstract":["Although immune checkpoint blockade (ICB) therapy can induce durable survival benefits in patients with advanced cancer, most patients do not respond. ICB acts by reinvigorating pre-existing anti-tumor immune responses, and responders are often characterized by the presence of a T cell infiltrate in tumors. However, T cell infiltration does not always correspond to ICB efficacy. Tumor-reactive T cells can acquire persistent dysfunctional states, which are resistant to ICB reinvigoration. Increasing evidence suggests that T cell dysfunction can arise during T cell priming. Dendritic cells (DCs) play a key role in priming tumor-reactive T cells, indicating that DC-derived signals could regulate the functional quality of anti-tumor T cell responses. In this work, we investigated how cancer-associated suppression of DCs could lead to dysfunctional anti-tumor T cell responses. First, we explored tissue-specific mechanisms that could mediate lung tumor-specific T cell dysfunction, previously found to be induced during T cell priming in the lung tumor-draining lymph node (tdLN). We determined that the T cell dysfunction was caused by regulatory T cell (Treg)-mediated suppression of DC stimulatory capacity. Suppression required direct contact between Tregs and DCs and was specifically associated with the presence of clonally-expanded T helper type 1 (TH1)-like Tregs. TH1-like Tregs were induced in response to elevated levels of interferon-gamma (IFNγ) in the lung tdLN. Administration of IFNγ-blocking antibody could counter the tissue-specific enrichment in IFNγ, repolarize Tregs and restore cytotoxic T cell responses against lung cancer. Next, we examined longitudinal changes in anti-tumor immunity associated with the observed decline in ICB efficacy in later-stages tumors. We found that ICB resistance at later timepoints was accompanied by T cell dysfunction and a decline in stimulatory DCs in both the tumor and tdLN. Treatment with Poly(I:C) could enhance T cell and DC responses at later timepoints, providing a clear rationale for combination immunotherapy using Poly(I:C) and ICB. Our work demonstrates that distinct tissue-specific and temporal elements can suppress DC ability to support productive anti-tumor immunity. Counteracting these mechanisms of DC dysfunction has the potential to enhance cytotoxic T cell responses and help better leverage the potential of anti-tumor immunity for long-term disease control."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["https://hdl.handle.net/1721.1/150065"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["In Copyright - Educational Use Permitted","Copyright MIT"],"dc:rights.uri":["http://rightsstatements.org/page/InC-EDU/1.0/"],"dc:title":["Dendritic cell dysfunction restrains cytotoxic T cell responses against cancer"],"dc:type":["Thesis"],"thesis:degree_name":["Doctoral","Doctor of Philosophy"]},"updated_at":"2026-07-22T22:21:25Z"}