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The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incomplet...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557252/ https://www.ncbi.nlm.nih.gov/pubmed/28807001 http://dx.doi.org/10.1186/s40425-017-0268-8 |
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author | Poon, Edmund Mullins, Stefanie Watkins, Amanda Williams, Geoffrey S. Koopmann, Jens-Oliver Di Genova, Gianfranco Cumberbatch, Marie Veldman-Jones, Margaret Grosskurth, Shaun E. Sah, Vasu Schuller, Alwin Reimer, Corrine Dovedi, Simon J. Smith, Paul D. Stewart, Ross Wilkinson, Robert W. |
author_facet | Poon, Edmund Mullins, Stefanie Watkins, Amanda Williams, Geoffrey S. Koopmann, Jens-Oliver Di Genova, Gianfranco Cumberbatch, Marie Veldman-Jones, Margaret Grosskurth, Shaun E. Sah, Vasu Schuller, Alwin Reimer, Corrine Dovedi, Simon J. Smith, Paul D. Stewart, Ross Wilkinson, Robert W. |
author_sort | Poon, Edmund |
collection | PubMed |
description | BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME). METHODS: In mice, the effects of MEK inhibition, via selumetinib, and anti-CTLA-4 on immune responses to keyhole limpet haemocyanin (KLH) immunization were monitored using ex vivo functional assays with splenocytes. In a KRAS-mutant CT26 mouse colorectal cancer model, the impact on the tumor microenvironment (TME) and the spleen were evaluated by flow cytometry. The TME was further examined by gene expression and immunohistochemical analyses. The combination and sequencing of selumetinib and anti-CTLA-4 were also evaluated in efficacy studies using the CT26 mouse syngeneic model. RESULTS: Anti-CTLA-4 enhanced the generation of KLH specific immunity following KLH immunization in vivo; selumetinib was found to reduce, but did not prevent, this enhancement of immune response by anti-CTLA-4 in vivo. In the CT26 mouse model, anti-CTLA-4 treatment led to higher expression levels of the immunosuppressive mediators, Cox-2 and Arg1 in the TME. Combination of anti-CTLA-4 with selumetinib negated this up-regulation of Cox-2 and Arg1, reduced the frequency of CD11(+) Ly6G(+) myeloid cells, and led to the accumulation of differentiating monocytes at the Ly6C(+) MHC(+) intermediate state in the tumor. We also report that MEK inhibition had limited impact on anti-CTLA-4-mediated increases in T-cell infiltration and T-cell activation in CT26 tumors. Finally, we show that pre-treatment, but not concurrent treatment, with selumetinib enhanced the anti-tumor activity of anti-CTLA-4 in the CT26 model. CONCLUSION: These data provide evidence that MEK inhibition can lead to changes in myeloid cells and immunosuppressive factors in the tumor, thus potentially conditioning the TME to facilitate improved response to anti-CTLA-4 treatment. In summary, the use of MEK inhibitors to alter the TME as an approach to enhance the activities of immune checkpoint inhibitors warrants further investigation in clinical trials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-017-0268-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5557252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55572522017-08-16 The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment Poon, Edmund Mullins, Stefanie Watkins, Amanda Williams, Geoffrey S. Koopmann, Jens-Oliver Di Genova, Gianfranco Cumberbatch, Marie Veldman-Jones, Margaret Grosskurth, Shaun E. Sah, Vasu Schuller, Alwin Reimer, Corrine Dovedi, Simon J. Smith, Paul D. Stewart, Ross Wilkinson, Robert W. J Immunother Cancer Research Article BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME). METHODS: In mice, the effects of MEK inhibition, via selumetinib, and anti-CTLA-4 on immune responses to keyhole limpet haemocyanin (KLH) immunization were monitored using ex vivo functional assays with splenocytes. In a KRAS-mutant CT26 mouse colorectal cancer model, the impact on the tumor microenvironment (TME) and the spleen were evaluated by flow cytometry. The TME was further examined by gene expression and immunohistochemical analyses. The combination and sequencing of selumetinib and anti-CTLA-4 were also evaluated in efficacy studies using the CT26 mouse syngeneic model. RESULTS: Anti-CTLA-4 enhanced the generation of KLH specific immunity following KLH immunization in vivo; selumetinib was found to reduce, but did not prevent, this enhancement of immune response by anti-CTLA-4 in vivo. In the CT26 mouse model, anti-CTLA-4 treatment led to higher expression levels of the immunosuppressive mediators, Cox-2 and Arg1 in the TME. Combination of anti-CTLA-4 with selumetinib negated this up-regulation of Cox-2 and Arg1, reduced the frequency of CD11(+) Ly6G(+) myeloid cells, and led to the accumulation of differentiating monocytes at the Ly6C(+) MHC(+) intermediate state in the tumor. We also report that MEK inhibition had limited impact on anti-CTLA-4-mediated increases in T-cell infiltration and T-cell activation in CT26 tumors. Finally, we show that pre-treatment, but not concurrent treatment, with selumetinib enhanced the anti-tumor activity of anti-CTLA-4 in the CT26 model. CONCLUSION: These data provide evidence that MEK inhibition can lead to changes in myeloid cells and immunosuppressive factors in the tumor, thus potentially conditioning the TME to facilitate improved response to anti-CTLA-4 treatment. In summary, the use of MEK inhibitors to alter the TME as an approach to enhance the activities of immune checkpoint inhibitors warrants further investigation in clinical trials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-017-0268-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-15 /pmc/articles/PMC5557252/ /pubmed/28807001 http://dx.doi.org/10.1186/s40425-017-0268-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Poon, Edmund Mullins, Stefanie Watkins, Amanda Williams, Geoffrey S. Koopmann, Jens-Oliver Di Genova, Gianfranco Cumberbatch, Marie Veldman-Jones, Margaret Grosskurth, Shaun E. Sah, Vasu Schuller, Alwin Reimer, Corrine Dovedi, Simon J. Smith, Paul D. Stewart, Ross Wilkinson, Robert W. The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title | The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title_full | The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title_fullStr | The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title_full_unstemmed | The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title_short | The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment |
title_sort | mek inhibitor selumetinib complements ctla-4 blockade by reprogramming the tumor immune microenvironment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557252/ https://www.ncbi.nlm.nih.gov/pubmed/28807001 http://dx.doi.org/10.1186/s40425-017-0268-8 |
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