Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction
Inhibitory checkpoint blockade therapy is an immunomodulatory strategy that results in the restoration of T cell functions, and its efficacy depends on the recognition of tumor cells for destruction. Considering the factors at play, one could propose that anti-tumor responses will not occur if tumor...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00699/full |
| _version_ | 1818519351599300608 |
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| author | Brianna Burke Catherine Eden Cynthia Perez Alex Belshoff Spencer Hart Lourdes Plaza-Rojas Michael Delos Reyes Kushal Prajapati Christina Voelkel-Johnson Elizabeth Henry Gopal Gupta Gopal Gupta José Guevara-Patiño |
| author_facet | Brianna Burke Catherine Eden Cynthia Perez Alex Belshoff Spencer Hart Lourdes Plaza-Rojas Michael Delos Reyes Kushal Prajapati Christina Voelkel-Johnson Elizabeth Henry Gopal Gupta Gopal Gupta José Guevara-Patiño |
| author_sort | Brianna Burke |
| collection | DOAJ |
| description | Inhibitory checkpoint blockade therapy is an immunomodulatory strategy that results in the restoration of T cell functions, and its efficacy depends on the recognition of tumor cells for destruction. Considering the factors at play, one could propose that anti-tumor responses will not occur if tumor cells are immunologically invisible to T cells. In this study, we tested a strategy based on the modulation of cancer cell's immunovisibility through HDAC inhibition. In a model (heterotopic and orthotopic) of mouse urothelial bladder cancer, we demonstrated that the use of intratumoral or intravesical HDACi in combination with systemic anti-PD-1 was effective at inducing curative responses with durable anti-tumor immunity capable of preventing tumor growth at a distal site. Mechanistically, we determined that protective responses were dependent on CD8 cells, but not NK cells. Of significance, in an in vitro human model, we found that fully activated T cells fail at killing bladder cancer cells unless tumor cells were pretreated with HDACi. Complementary to this observation, we found that HDACi cause gene deregulation, that results in the upregulation of genes responsible for mediating immunorecognition, NKG2D ligands and HSP70. Taken together, these data indicate that HDAC inhibition results in the elimination of the tumor cell's “invisibility cloak” that prevents T cells from recognizing and killing them. Finally, as checkpoint blockade therapy moves into the adjuvant setting, its combined use with locally administrated HDACi represents a new approach to be included in our current therapeutic treatment toolbox. |
| first_indexed | 2024-12-11T01:23:07Z |
| format | Article |
| id | doaj.art-70a96232c7254b679693b5705a96ac6d |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T01:23:07Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-70a96232c7254b679693b5705a96ac6d2022-12-22T01:25:40ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-05-011010.3389/fonc.2020.00699517570Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated DestructionBrianna Burke0Catherine Eden1Cynthia Perez2Alex Belshoff3Spencer Hart4Lourdes Plaza-Rojas5Michael Delos Reyes6Kushal Prajapati7Christina Voelkel-Johnson8Elizabeth Henry9Gopal Gupta10Gopal Gupta11José Guevara-Patiño12Department of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Urology, Loyola University Medical Center, Maywood, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Urology, Loyola University Medical Center, Maywood, IL, United StatesDepartment of Urology, Loyola University Medical Center, Maywood, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Oncology, Loyola University Medical Center, Maywood, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesDepartment of Urology, Loyola University Medical Center, Maywood, IL, United StatesDepartment of Surgery and Cancer Biology, Loyola University Chicago, Chicago, IL, United StatesInhibitory checkpoint blockade therapy is an immunomodulatory strategy that results in the restoration of T cell functions, and its efficacy depends on the recognition of tumor cells for destruction. Considering the factors at play, one could propose that anti-tumor responses will not occur if tumor cells are immunologically invisible to T cells. In this study, we tested a strategy based on the modulation of cancer cell's immunovisibility through HDAC inhibition. In a model (heterotopic and orthotopic) of mouse urothelial bladder cancer, we demonstrated that the use of intratumoral or intravesical HDACi in combination with systemic anti-PD-1 was effective at inducing curative responses with durable anti-tumor immunity capable of preventing tumor growth at a distal site. Mechanistically, we determined that protective responses were dependent on CD8 cells, but not NK cells. Of significance, in an in vitro human model, we found that fully activated T cells fail at killing bladder cancer cells unless tumor cells were pretreated with HDACi. Complementary to this observation, we found that HDACi cause gene deregulation, that results in the upregulation of genes responsible for mediating immunorecognition, NKG2D ligands and HSP70. Taken together, these data indicate that HDAC inhibition results in the elimination of the tumor cell's “invisibility cloak” that prevents T cells from recognizing and killing them. Finally, as checkpoint blockade therapy moves into the adjuvant setting, its combined use with locally administrated HDACi represents a new approach to be included in our current therapeutic treatment toolbox.https://www.frontiersin.org/article/10.3389/fonc.2020.00699/fullHDACbladder cancerT cellsNKG2Danti-PD1immune evasion |
| spellingShingle | Brianna Burke Catherine Eden Cynthia Perez Alex Belshoff Spencer Hart Lourdes Plaza-Rojas Michael Delos Reyes Kushal Prajapati Christina Voelkel-Johnson Elizabeth Henry Gopal Gupta Gopal Gupta José Guevara-Patiño Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction Frontiers in Oncology HDAC bladder cancer T cells NKG2D anti-PD1 immune evasion |
| title | Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction |
| title_full | Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction |
| title_fullStr | Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction |
| title_full_unstemmed | Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction |
| title_short | Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction |
| title_sort | inhibition of histone deacetylase hdac enhances checkpoint blockade efficacy by rendering bladder cancer cells visible for t cell mediated destruction |
| topic | HDAC bladder cancer T cells NKG2D anti-PD1 immune evasion |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00699/full |
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