CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models
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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. Cancer Res; 74(18); 5057–69. ©2014 AACR.
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TAMs arising from tissue-resident macrophages or circulating monocytes play important but potentially different roles in shaping the TME and suppressing adaptive immunity.
“Tumor-associated macrophages (TAMs) arising from both tissue resident macrophages or circulating monocytes appear to play important but potentially different roles in shaping the TME, and suppression of the adaptive immune response178”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [178]
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- Authors
- Zhu, Y., Knolhoff, B. L., Meyer, M. A., Nywening, T. M., West, B. L., Luo, J., Wang-Gillam, A., Goedegebuure, S. P., Linehan, D. C., & DeNardo, D. G.
- Affiliations
- Washington University in St. Louis (US)
- Plexxikon (United States) (US)
- 1Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
- Corresponding author
- DeNardo, David G.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-09-14
- Volume
- 74
- Issue
- 18
- Pages
- 5057-5069
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4182950
- OpenAlex
- W1997944395
- Cited by
- 1,324
- References
- 45
- Citations by year
- 2026: 105 · 2025: 93 · 2024: 105 · 2023: 134 · 2022: 144 · 2021: 161 · 2020: 150 · 2019: 120 · 2018: 107 · 2017: 83 · 2016: 74 · 2015: 37 · 2014: 8 · 2013: 1
- FWCI
- 30.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (KL2TR000450, UL1TR000448)
- National Cancer Institute (P30 CA 91842, R21CA182701, R01CA168863, R01CA177670, T32CA009621, T32CA113275, P30CA091842)
- National Center for Research Resources (KL2RR024994, UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- CSF1R blockade, CSF-1, tumor-associated macrophages, macrophage reprogramming, pancreatic ductal adenocarcinoma, tumor microenvironment, myeloid-derived suppressor cells, PD-1, CTLA-4, PD-L1, combination immunotherapy, antigen presentation, immune evasion
- MeSH terms
- Mannose Receptor, Gemcitabine, Adenocarcinoma, Animals, Deoxycytidine, Female, Humans, Immunotherapy, Macrophages, Mice, Inbred C57BL, Pancreatic Neoplasms, Random Allocation, Receptors, Cell Surface, T-Lymphocytes, Cohort Studies, Signal Transduction, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Carcinoma, Pancreatic Ductal, Lectins, C-Type, Mannose-Binding Lectins, Tissue Array Analysis, Mice, Tumor Microenvironment
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