Using a combination of surface marker expression, single-cell RNA sequencing, and single-cell secretion analysis, Perry et al. distinguished changes in multiple tumor-associated macrophage populations (TAMs) in uninflamed autochthonous BRAF/PTEN melanoma tumors treated with agonist CD40 and a CSFR1 inhibitor. They demonstrated a shift to an inflammatory polyfunctional macrophage population, which resulted in synergistic tumor control that was dependent on T cells, TNFα, and IFNγ.
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.
Author Info: (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 Path
Author Info: (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) Department of Biomedical Engineering, Yale University, New Haven, CT. (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT. Howard Hughes Medical Institute, Chevy Chase, MD. (6) Department of Pathology, Yale University School of Medicine, New Haven, CT. (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT. (8) Department of Pathology, Yale University School of Medicine, New Haven, CT. (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT. Department of Pathology, Yale University School of Medicine, New Haven, CT. (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT. (11) Department of Biomedical Engineering, Yale University, New Haven, CT. (12) Department of Pathology, Yale University School of Medicine, New Haven, CT. (13) Department of Biomedical Engineering, Yale University, New Haven, CT kathryn.miller-jensen@yale.edu. (14) Department of Immunobiology, Yale University School of Medicine, New Haven, CT susan.kaech@yale.edu.
