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J Exp Med. 2018 Mar 5;215(3):877-893. doi: 10.1084/jem.20171435. Epub 2018 Feb 7.

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
2
Department of Biomedical Engineering, Yale University, New Haven, CT.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT.
4
Howard Hughes Medical Institute, Chevy Chase, MD.
5
Department of Biomedical Engineering, Yale University, New Haven, CT kathryn.miller-jensen@yale.edu.
6
Department of Immunobiology, Yale University School of Medicine, New Haven, CT susan.kaech@yale.edu.

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.

PMID:
29436395
PMCID:
PMC5839759
DOI:
10.1084/jem.20171435
[Indexed for MEDLINE]
Free PMC Article

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