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Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy
Open accessAbstract
Preventing trafficking of myeloid-derived suppressor cells to the tumor site enhances the efficiency of checkpoint blockade.
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“Notably, data from various mouse models indicate that disrupting the CXCR1/2–MDSC axis in tumours is therapeutically efficacious across a wide variety of solid cancers166–172.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [168]
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“These results are consistent with previous reports demonstrating that GrMDSCs at the tumor site are highly dependent on migration from the BM or spleen and undergo minimal proliferation within the tumor bed (13).”
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“Recent studies have illuminated the potential of targeting MDSCs in other cancers to activate anti-tumor immune responses and amplify the effectiveness of ICTs [71,72].”
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“Also, in tumor tissue, MDSCs are believed to play an important role in inhibiting immune responses by T cells and natural killer cells, and elevated MDSC infiltration is correlated with a poor prognosis and resistance to therapy (27-30).”
BackgroundAdoptive neoantigen-reactive T cell therapy: improvement strategies and current clinical researches
Huang, R., Bi, Z., Hu, S., Zhang, Q., Su, X., & Zhang, W. (2023) · Biomarker Research · doi:10.1186/s40364-023-00478-5 · Cited by 15
“For MDSCs, gemtuzumab can deplete intratumoral MDSCs, and the CXCR2 antagonist can block migration of MDSCs into tumors [139, 140].”
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“CCR2 and CXCR2 are key chemotactic receptors for M-MDSCs and PMN-MDSCs, respectively [47, 104, 105].”
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New Discovery of Myeloid-Derived Suppressor Cell’s Tale on Viral Infection and COVID-19
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Modulation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment by Natural Products
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“A second therapeutic approach involves using anti-CXCR2 or CCR2 monoclonal antibodies to reduce MDSCs infiltration in the TME, which have shown some effectiveness in murine models (Draghiciu et al. 2015; Highfill et al. 2014; Zeng et al. 2019).”
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“In cancer models, the migration of MDSCs to tumor sites is driven by the chemokine receptor CXCR2 in response to CXCL1/CXCL2 (18, 19).”
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Roles of tissue-resident immune cells in immunotherapy of non-small cell lung cancer
Tang, R., Wang, H., & Tang, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1332814 · Cited by 13
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“More specifically, it was concluded that epigenetic modifiers, such as LD-AET with CCR2-antagonists, in combination with tumour resection, may mitigate the migration and function of MDSCs in the lung PMN (Lu et al. 2020; Highfill et al. 2014).”
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“They tested this hypothesis by combining a CXCR2 inhibitor with an anti-PD1 antibody in KPC mice with end-stage, palpable disease, an approach that has shown therapeutic benefit in other cancer models (Highfill et al., 2014).”
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“On the contrary, the loss of MDSCs within the tumor could restore the effectiveness of PD-1 blockade [61, 62].”
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“Interestingly, in this study, PD-1 blockade therapy showed limited tumor growth inhibition effects when initiated later in the tumor development process [67].”
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Zhao, T., Liu, S., Hanna, N. H., Jalal, S. I., Ding, X., Wan, J., Yan, C., & Du, H. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006272 · Cited by 11
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“Tumor cells secrete ligands CCL5, CCL7, and CX-C motif chemokine ligand 8, and bind to the receptor CC motif chemokine receptor (CCR) 1 or C-X-C chemokine receptor 2 expressed on the MDSCs subtype to recruit MDSCs into the tumor microenvironment.([34]) Tregs selectively over-express the chemokine CCR4, and its specifi…”
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“CXCR2 deficiency prevents MDSC trafficking and enhances anti- PD1 efficacy (Highfill et al., 2014).”
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“Notably, several MDSC-targeting agents and the blockade of MDSC-inducing cytokines or chemokines have been confirmed to potentiate antitumor immune responses and reverse immune resistance to ICIs in patients with cancer [53–55].”
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“Several of these potential inhibitors have shown the minimal to broad effect on MDSCs [31,33-35].”
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Inhibition of hexokinase 2 with 3-BrPA promotes MDSCs differentiation and immunosuppressive function
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“Accordingly, disrupting CXCR2-mediated MDSC trafficking to the TME was shown to enhance anti-PD-1 therapy response in a murine model of rhabdomyosarcoma [29].”
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“Highfil et al.[71] have shown in a murine model of rhabdomyosarcoma that CXCL-1 and CXCL-2 are responsible for the trafficking of MDSCs into the tumor.”
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“Therefore, the clinical benefits of immune checkpoint therapy in patients with tumors are significantly reduced [49].”
BackgroundNAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer
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Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress
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“Targeting CXCR2 also augments the therapeutic efficacy of PD-1 blockade (Highfill et al., 2014; Zhang et al., 2020).”
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Phenotypic and Functional Diversity of Neutrophils in Gut Inflammation and Cancer
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“A previous study with murine rhabdomyosarcoma showed that CXCR2‐positive MDSCs inhibited the antitumor effect of anti‐PD‐1 antibody treatment and that anti‐CXCR2 monoclonal antibody therapy enhanced it (30,31).”
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“Third, Dec notably decreased vegf, and Cxcr2 gene expression, limiting MDSC migration from bone marrow to tumors [32].”
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“In line with this hypothesis, we and others have demonstrated that blocking PMN-MDSC trafficking into the tumor augments responses to immune checkpoint blockade.(34,37) In addition, the rationale for targeting these cells in combination with other immune therapeutic interventions has also been supported by studies usi…”
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Metadata
- Authors
- Highfill, S. L., Cui, Y., Giles, A. J., Smith, J. P., Zhang, H., Morse, E., Kaplan, R. N., & Mackall, C. L.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Mackall, Crystal L.
- Venue
- Science Translational Medicine
- Published
- 2014-05-21
- Volume
- 6
- Issue
- 237
- Pages
- 237ra67-237ra67
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC6980372
- OpenAlex
- W2171524684
- Cited by
- 767
- References
- 50
- Citations by year
- 2026: 55 · 2025: 62 · 2024: 57 · 2023: 83 · 2022: 73 · 2021: 100 · 2020: 91 · 2019: 60 · 2018: 52 · 2017: 52 · 2016: 38 · 2015: 31 · 2014: 12
- FWCI
- 20.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC011072, Z01BC010566, Z01SC010289)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- CXCR2, myeloid-derived suppressor cells, tumor immune evasion, anti-PD-1 therapy, rhabdomyosarcoma, pediatric sarcoma, interleukin-8, PD-L1, tumor immunosuppression
- MeSH terms
- Adolescent, Adult, Animals, Antibodies, Monoclonal, Antigens, Ly, Antineoplastic Combined Chemotherapy Protocols, Chemotaxis, Child, Child, Preschool, Female, Humans, Male, Mice, Inbred C57BL, Prognosis, Rhabdomyosarcoma, Time Factors, Neoplastic Stem Cells, Case-Control Studies, Cytokines, Interleukin-8, Mice, Knockout, Tumor Escape, Receptors, Interleukin-8B, CD11b Antigen, Cell Line, Tumor, Tumor Burden, Mice, Chemokine CXCL1, Young Adult, Tumor Microenvironment, B7-H1 Antigen
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