Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma
Open accessAbstract
Background: Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). Methods: To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Results: Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Conclusion: Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
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Depletion of macrophages through a CSF-1R inhibitor has shown efficacy in a glioblastoma mouse model.
“Their depletion through a Colony stimulating factor-1 receptor (CSF-1R) inhibitor is therefore being explored in clinical trials together with anti-PD-1, after having shown efficacy in a glioblastoma mouse model (119).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [119]
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- Pyonteck SM, Akkari L, Schuhmacher AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19(10):1264-1272.
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- Authors
- Antonios, J. P., Soto, H., Everson, R. G., Moughon, D., Orpilla, J. R., Shin, N. P., Sedighim, S., Treger, J., Odesa, S., Tucker, A., Yong, W. H., Li, G., Cloughesy, T. F., Liau, L. M., & Prins, R. M.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-01-23
- Volume
- 19
- Issue
- 6
- Pages
- now287
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC5464463
- OpenAlex
- W2581747126
- Cited by
- 206
- References
- 48
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 30 · 2023: 21 · 2022: 26 · 2021: 29 · 2020: 19 · 2019: 24 · 2018: 19 · 2017: 11
- FWCI
- 9.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuro-Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R21CA186004, P50CA211015, P30CA016042)
- National Institute of Allergy and Infectious Diseases (P30AI028697)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK041301)
- National Institute of Neurological Disorders and Stroke (R25NS079198)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- glioblastoma, tumor-infiltrating myeloid cells, adaptive immune resistance, PD-1/PD-L1 signaling, dendritic cell vaccine, tumor-infiltrating lymphocytes, CSF1R inhibitor, PLX3397, anti-PD-1 monoclonal antibody, tumor microenvironment, chemoattractants, immunotherapy
- MeSH terms
- Animals, Antibodies, Monoclonal, Female, Glioblastoma, Humans, Mice, Inbred C57BL, Tumor Cells, Cultured, Receptor, Macrophage Colony-Stimulating Factor, Lymphocytes, Tumor-Infiltrating, Cancer Vaccines, Myeloid Cells, Xenograft Model Antitumor Assays, Mice, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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