title: CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models.
abstract: Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Knolhoff
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Meyer
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Nywening
authors.affiliation: Plexxikon Inc., Berkeley, California.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Goedegebuure
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri. ddenardo@dom.wustl.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment; D000093542:Gemcitabine
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D003841:Deoxycytidine; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000093542:Gemcitabine
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