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 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.