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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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BackgroundTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
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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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“Inhibition of CXCR with small-molecule inhibitors has shown promise in improving outcomes in STS and enhancing the activity of programmed cell death protein 1 (PD-1) inhibitors [44, 45].”
Response Challenges to Cancer Immunotherapies
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Nanoparticle accumulation in liver may induce resistance to immune checkpoint blockade therapy
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BackgroundNovel CXCR2 antibodies exhibit enhanced anti-tumor activity in pancreatic cancer
Rahimizadeh, P., Kim, S., Yoon, B. J., Jeong, Y. S., Lim, S., Jeon, H., Lim, H. J., Park, S. H., Park, S., Kong, D.-H., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117966 · Cited by 5
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“This outcome suggests that therapy targeting, in part, chemokine receptor pathways including Cxcl1/Cxcr2, may be an effective approach for reducing or preventing the tumor-promoting effect of the inflammatory TME [25, 26].”
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Emerging hallmark of gliomas microenvironment in evading immunity: a basic concept
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“CXCL8 expression by GBM has been shown to regulate the entry of MDSCs into the tumor environment via the CXCR2 receptor [125].”
BackgroundThe Role of Myeloid Derived Suppressor Cells in Urothelial Carcinoma Immunotherapy
Puttmann, K. T., Duggan, M. C., Mortazavi, A., Diaz, D. A., Carson, W. E., & Sundi, D. (2019) · Bladder Cancer · doi:10.3233/blc-190219 · Cited by 5
“MDSC targeting approaches in these studies have included histamine [61] TGF inhibition, [62] phenformin (an anti-diabetic biguanide) [63] CXCR2 inhibition, [64] sorafenib, [41] all-trans-retinoic-acid (ATRA), [65] ibrutinib (an inhibitor of the Bruton’s tyrosine kinase pathway in MDSC), [66] inhibition of”
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CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk
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“CXCL5 has also been studied as a therapeutic target for the prevention of tumor angiogenesis or as an enhancer of cancer drug efficacy [74, 75].”
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Prostate Cancer Immunotherapy: Time to Move Beyond Checkpoint Inhibitors
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“79 As with IL-8, CXCR2 binding can allow MDSCs to promote tumor growth.”
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“In an interesting study that tested timing of checkpoint therapy administration, targeting PD-1 is only effective when given very early after tumor initiation, unless CXCR2 signaling is blocked; with CXCR2 blockade, there is lower myeloid-derived suppressor cell infiltration into the TME, which restores the efficacy o…”
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“14 The inhibition of FATP2 abrogated the suppressive functions of PMN-MDSCs and sensitised anti-CTLA4 antibody treatment.”
BackgroundRole of myeloid cells in the tumor microenvironment
Balakrishnan, A., Vig, M., & Dubey, S. (2022) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2022.33 · Cited by 4
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“…via JAK/STAT1 signaling [7], addressing antigen presentation deficiencies in TNBC. (2) GM-CSF, the cytokine payload in FDA-approved T-VEC for melanoma [8], promotes DC recruitment and maturation, but in breast cancer models, it has also been implicated in MDSC expansion and tumor progression [9].”
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“Consistent with this observation, we found decreased hepatic neutrophil and myeloid cell/macrophage infiltration in TRPV4 KO mice as indicated by differential expression of the genes: S100a8/a9 (79), Cd177 (52) , Mmp8 (80) , Mpo (50) , Elane (49), and Cxcr2 (60, 81, 82).”
Chen, H., Huang, Y., Wu, Yi, Z., Li, Y., Yang, Z., Zhang, F., & Li, C. (2026) · Advanced Science · doi:10.1002/advs.202523331 · Cited by 3
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“These blood-and tissue-based readouts also support pharmacodynamic endpoints for CXCR1/2 blockade or IL-8-axis targeting, including rational combinations with ICIs (47, 48).”
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“For example, in pancreatic adenocarcinoma, NF-κ B-driven expression of CXCL5 fosters tumor progression via recruitment of CXCR2 + myeloid-derived suppressor cells (MDSC) and tumor-associated neutrophils [43,44].”
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“71 72 Additionally, inhibiting CD300ld on the surface of neutrophils has been shown to improve the antitumour efficacy of anti- PD-1 treatment.”
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“Inflammation also recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) [79], which, in turn, attenuate the effectiveness checkpoint blockade therapy [80,81].”
BackgroundRole of the CXCL8–CXCR1/2 Axis in Cancer and Inflammatory Diseases
Mir, M. A., Bashir, M., & Ishfaq, I. (2023) · Springer eBooks · doi:10.1007/978-981-99-4657-0_11 · Cited by 2
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“Some genes have been associated with synergistically dampening immune response with PD-L1/PD-1 checkpoint axis (Trem2 [Molgora et al., 2020], Mertk and Gas6 [Holtzhausen et al., 2019; Lee-Sherick et al., 2018], CD38 [Chen et al., 2018], C1q [Roumenina et al., 2019a, 2019b]); regulatory T cell recruitment/induction (CC…”
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“Moreover, previous study by Martin et al. also showed that hypoxia signaling and glycolysis-related pathways are upregulated in HCCs insensitive to TACE, and targeting PKM2, an HIF-1α-related gene, could improve the response rate to TACE [73].”
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Chhabra, G., Su, S., Shirley, C. A., Thornton, J., Rizvi, H. A., Robarge, R. K., Krien, J. M., Ndiaye, M. A., & Ahmad, N. (2025) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2025.07.009 · Cited by 1
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“…vulnerabilities such as defects in DNA Damage Repair (DDR) Pathways (e.g., in BRCA1/2) with Poly (ADP-ribose) polymerases (PARPs) inhibitors, and investigating strategies against aberrant WNT/ β -catenin signaling, are critical for developing more effective and personalized treatments 21,22 .”
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“Blocking this pathway not only reduces suppressive myeloid infiltration but also restores CTL-driven tumor clearance, demonstrating that effective therapy requires simultaneous suppression of anti-viral-induced immuno-suppression [28 ].”
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“Indeed, CXCR2 inhibitors have shown promise in preclinical models by improving T-cell infiltration and enhancing checkpoint blockade therapy, as well as targeting inflammatory tumor-derived cytokines (such as GM-CSF, G-CSF, IL-6) [100].”
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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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