Pfirschke et al. studied the effects of blocking CSF1R signaling in a lung carcinoma mouse model, KP1.9, to elucidate the role of tumor-associated macrophages in suppressing tumor growth. The effects of the intraperitoneal small molecule CSF1R inhibitor BLZ945 were investigated using scRNAseq, which revealed tumor control was not due to CSF1R+ cell depletion or modulation of pro- and anti-inflammatory macrophage subsets, but due to cross-talk with CSF1R- cells. Tumor control was dependent on IFNγ-producing NK and T cells, and a unique IL-12-producing, tumor-infiltrating, activated dendritic cell subset, DC3. This subset was conserved between humans and mice.
Contributed by Katherine Turner
ABSTRACT: Macrophages often abound within tumors, express colony-stimulating factor 1 receptor (CSF1R), and are linked to adverse patient survival. Drugs blocking CSF1R signaling have been used to suppress tumor-promoting macrophage responses; however, their mechanisms of action remain incompletely understood. Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches. We showed that tumor control was not caused by CSF1R+ cell depletion; instead, CSF1R targeting reshaped the CSF1R+ cell landscape, which unlocked crosstalk between antitumoral CSF1R- cells. These cells included IFNγ-producing NK and T cells, and an IL12-producing dendritic cell subset, denoted as DC3, which were all necessary for CSF1R inhibitor-mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal crosstalk between cells that are not macrophages and that are essential to mediate the effects of T cell-targeted immunotherapies and promote antitumor immunity.
Author Info: (1) Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School. (2) Life Sciences Center, Department of Biotechnology, Vilnius University. (3) Dept of Ce
Author Info: (1) Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School. (2) Life Sciences Center, Department of Biotechnology, Vilnius University. (3) Dept of Cell and Molecular Biology, Karolinska Institutet. (4) Massachusetts General Hospital and Harvard Medical School. (5) Massachusetts General Hospital and Harvard Medical School. (6) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology. (7) Systems Biology, Harvard Medical School. (8) Massachusetts General Hospital and Harvard Medical School. (9) Massachusetts General Hospital/Harvard Medical School. (10) Massachusetts General Hospital/Harvard Medical School. (11) Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School. (12) Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School. (13) Massachusetts General Hospital and Harvard Medical School. (14) School of Biomedical Engineering, Science and Health Systems, Drexel University. (15) Chemistry, Northeastern University. (16) Massachusetts General Hospital/Harvard Medical School. (17) Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School. (18) Center for Molecular Imaging Research, Mass General Hospital. (19) Harvard University. (20) Center for Systems Biology, Massachusetts General Hospital/Harvard Medical School. (21) Systems Biology, Harvard University. (22) Pathology and Immunology, University of Geneva Mikael.Pittet@unige.ch.
