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Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity

Authors :
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.
Source :
The Journal of Experimental Medicine; March 2018, Vol. 215 Issue: 3 p877-893, 17p
Publication Year :
2018

Abstract

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.

Details

Language :
English
ISSN :
00221007 and 15409538
Volume :
215
Issue :
3
Database :
Supplemental Index
Journal :
The Journal of Experimental Medicine
Publication Type :
Periodical
Accession number :
ejs44954314
Full Text :
https://doi.org/10.1084/jem.20171435