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Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity
Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839759/ https://www.ncbi.nlm.nih.gov/pubmed/29436395 http://dx.doi.org/10.1084/jem.20171435 |
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author | Perry, Curtis J. Muñoz-Rojas, Andrés R. Meeth, Katrina M. Kellman, Laura N. Amezquita, Robert A. Thakral, Durga Du, Victor Y. Wang, Jake Xiao Damsky, William Kuhlmann, Alexandra L. Sher, Joel W. Bosenberg, Marcus Miller-Jensen, Kathryn Kaech, Susan M. |
author_facet | Perry, Curtis J. Muñoz-Rojas, Andrés R. Meeth, Katrina M. Kellman, Laura N. Amezquita, Robert A. Thakral, Durga Du, Victor Y. Wang, Jake Xiao Damsky, William Kuhlmann, Alexandra L. Sher, Joel W. Bosenberg, Marcus Miller-Jensen, Kathryn Kaech, Susan M. |
author_sort | Perry, Curtis J. |
collection | PubMed |
description | Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a “cold” into an “inflamed” tumor microenvironment capable of eliciting protective T cell responses. |
format | Online Article Text |
id | pubmed-5839759 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58397592018-09-05 Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity Perry, Curtis J. Muñoz-Rojas, Andrés R. Meeth, Katrina M. Kellman, Laura N. Amezquita, Robert A. Thakral, Durga Du, Victor Y. Wang, Jake Xiao Damsky, William Kuhlmann, Alexandra L. Sher, Joel W. Bosenberg, Marcus Miller-Jensen, Kathryn Kaech, Susan M. J Exp Med Research Articles Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a “cold” into an “inflamed” tumor microenvironment capable of eliciting protective T cell responses. Rockefeller University Press 2018-03-05 /pmc/articles/PMC5839759/ /pubmed/29436395 http://dx.doi.org/10.1084/jem.20171435 Text en © 2018 Perry et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Perry, Curtis J. Muñoz-Rojas, Andrés R. Meeth, Katrina M. Kellman, Laura N. Amezquita, Robert A. Thakral, Durga Du, Victor Y. Wang, Jake Xiao Damsky, William Kuhlmann, Alexandra L. Sher, Joel W. Bosenberg, Marcus Miller-Jensen, Kathryn Kaech, Susan M. Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title | Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title_full | Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title_fullStr | Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title_full_unstemmed | Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title_short | Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
title_sort | myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839759/ https://www.ncbi.nlm.nih.gov/pubmed/29436395 http://dx.doi.org/10.1084/jem.20171435 |
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