Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 3, Pages 877-893Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171435
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Funding
- Yale School of Medicine Medical Scientist Training Program [NIH/NIG MS T32 GM007205]
- Yale Specialized Programs of Research Excellence in Skin Cancer [5 P50 CA121974]
- Wade F.B. Thompson/Cancer Research Institute-Clinic and Laboratory Integration Progarm grant
- Oliver R. Grace and Wade F.B. Thompson Cancer Research Institute-CLIP grants
- Melanoma Research Alliance grant
- Melanoma Research Foundation
- Yale Cancer Center Co-Pilot grant
- National Institutes of Health [1 R01 GM123011-01]
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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-alpha, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-alpha and IFN-gamma. 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.
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