Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity
2018
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 therapywith an agonistic anti-
CD40mAb 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
MMP9or cosecreting
CCL17/22, characteristic of an M2-like state.
Combination therapyreduced 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 therapywas 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 microenvironmentcapable of eliciting protective T cell responses.
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