2026-09-19T14:43:50Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/1500652023-04-01T03:39:33Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Spranger, Stefani
Zagorulya, Maria
Massachusetts Institute of Technology. Department of Biology
2023-03-31T14:29:24Z
2023-03-31T14:29:24Z
2023-02
2023-03-03T06:02:29.759Z
https://hdl.handle.net/1721.1/150065
0000-0002-4478-5378
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.
Ph.D.
Massachusetts Institute of Technology
In Copyright - Educational Use Permitted
Copyright MIT
http://rightsstatements.org/page/InC-EDU/1.0/
Dendritic cell dysfunction restrains cytotoxic T cell responses against cancer
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<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>
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