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

CJ Perry, AR Muñoz-Rojas, KM Meeth… - Journal of Experimental …, 2018 - rupress.org
CJ Perry, AR Muñoz-Rojas, KM Meeth, LN Kellman, RA Amezquita, D Thakral, VY Du…
Journal of Experimental Medicine, 2018rupress.org
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 …
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.
rupress.org