We have located links that may give you full text access.
HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma.
Clinical Cancer Research 2016 August 16
PURPOSE: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.
EXPERIMENTAL DESIGN: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.
RESULTS: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.
CONCLUSIONS: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119-32. ©2016 AACR.
EXPERIMENTAL DESIGN: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.
RESULTS: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.
CONCLUSIONS: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119-32. ©2016 AACR.
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app