Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
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
_version_ 1783304456110080000
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
work_keys_str_mv AT perrycurtisj myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT munozrojasandresr myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT meethkatrinam myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT kellmanlauran myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT amezquitaroberta myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT thakraldurga myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT duvictory myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT wangjakexiao myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT damskywilliam myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT kuhlmannalexandral myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT sherjoelw myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT bosenbergmarcus myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT millerjensenkathryn myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity
AT kaechsusanm myeloidtargetedimmunotherapiesactinsynergytoinduceinflammationandantitumorimmunity