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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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“Furthermore, studies on rhabdomyosarcoma in mice have shown that disruption of CXCR2-dependent MDSC trafficking to the tumor resulted in significantly increased antitumor effects [79].”
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“reported that CXCR2 is required for the trafficking of MDSCs to the tumour bed and that inhibiting MDSC trafficking to the tumour enhanced the potency of PD1 checkpoint blockade.(48)”
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“These immature myeloid cells can be phenotypically divided into early-MDSCs (e-MDSCs), monocytic MDSCs (M-MDSCs), and polymorphonuclear MDSCs (PMN-MDSCs) [60,61].”
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“The efficacy of anti-PD-1 treatment was improved by genetic deficiency or inhibition of CXCR1/2 in murine models of oral and lung carcinomas, rhabdomyosarcomas [136], pancreatic adenocarcinoma [147], and prostate cancer [155].”
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“Increased CXCR2 expression is associated with increased MDSC infiltration, angiogenesis, and therapeutic resistance in multiple cancers, including lung and pancreatic cancers [46].”
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“The massive accumulation of MDSCs in tumor tissues will limit the inhibitory effect of ICIs on tumors (38).”
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“These data are consistent with prior reports that inhibition of CXCR2 reduces tumor MDSC infiltration and tumor growth in cancer models (64–67) and improved the efficacy of PD-1 immune checkpoint blockade (68, 69).”
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“, 2012), and when disrupted, MDSC trafficking enhances anti-PD1 therapy (Highfill et al., 2014).”
BackgroundS100A10 promotes cancer metastasis via recruitment of MDSCs within the lungs
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“38,39 The function of the CXCL1 and CXCL8 is chemotactic for MDSCs, neutrophils, and monocytes and remodels the immune micro-environment of the tumor.”
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“CXCR2 also induces the migration of MDSCs, thus, promoting local immunosuppression (107).”
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“CXCR2 is involved in the formation of premetastatic niche in the liver of PDAC through G-proteincoupled receptors that control neutrophil and MDSCs migration (110).”
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“Meyer et al suggested that frequency of MDSCs may be a predictive marker of response, as low frequencies identify patients more likely to benefit from ipilimumab.”
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“Frontiers in Immunology 17 cell types, on their own and cooperatively, induce an immunesuppressive TME that prevents anti-tumor cytotoxic and Th1directed T-cell activities, mainly through the release of cytokines, chemokines, and other soluble mediators (113).”
BackgroundAnalysis of Immune Resistance Mechanisms in TNBC: Dual Effects Inside and Outside the Tumor
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The chemokine receptor CXCR2 contributes to murine adipocyte development
Dyer, D. P., Nebot, J. B., Kelly, C. J., Medina‐Ruiz, L., Schuette, F., & Graham, G. J. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.1a0618-216rr · Cited by 18
Wang, R., Ji, P., Gong, Y., Shao, Z., & Chen, S. (2020) · Breast Cancer Research and Treatment · doi:10.1007/s10549-020-05660-z · Cited by 18
Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells
Giudice, A. M., Roth, S. L., Matlaga, S., Cresswell-Clay, E., Mishra, P., Schürch, P. M., Boateng-Antwi, K. A. M., Samanta, M., Pascual‐Pasto, G., Zecchino, V. P., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.05.025 · Cited by 19
Kang, K., Liu, S., Yao, Z., Xue, J., & Lu, Y. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102315 · Cited by 17
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Wang, H., Yang, F.-C., Yang, C., Liu, Y., Ko, P., Li, C.-J., Tsai, C., Chung, Y., & Chen, N. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00399-x · Cited by 18
“Recent studies have spotlighted myeloid-derived suppressive cells (MDSCs) as one of the culprits in impairing the function of CTLs and attenuating the effectiveness of immunotherapies [7–11]; inhibition of trafficking MDSCs into tumor sites could enhance the efficacy of immunotherapies [12].”
BackgroundMagagnoli, J., Narendran, S., Pereira, F., Cummings, T. H., Hardin, J. W., Sutton, S. S., & Ambati, J. (2023) · Pharmaceuticals · doi:10.3390/ph16050640 · Cited by 16
Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis
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PD-1/PD-L1 blockade in paediatric cancers: What does the future hold?
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Emergency myelopoiesis contributes to immune cell exhaustion and pulmonary vascular remodelling
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Richard, S. A. (2020) · Disease Markers · doi:10.1155/2020/8844313 · Cited by 17
“Also, studies have demonstrated that GBM was capable of secreting IL-8 which in turn triggered the trafficking of MDSCs into the tumor environment via the CXCR2 receptor which functions as MIF receptors [36, 38].”
BackgroundThe Role of Myeloid-Derived Suppressor Cells in Tumor Growth and Metastasis
Bayık, D., Lee, J., & Lathia, J. D. (2022) · Experientia supplementum · doi:10.1007/978-3-030-91311-3_7 · Cited by 17
Akter, Z., Salamat, N., Ali, M. Y., & Li, Z. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1072739 · Cited by 17
Sun, S. H., Angell, C. D., Savardekar, H., Sundi, D., Abood, D., Benner, B. N., DiVincenzo, M. J., Duggan, M. C., Choueiry, F., Mace, T. A., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03497-1 · Cited by 16
“Other strategies to enhance the therapeutic efficacy of immune checkpoint blockade via inhibition of MDSC have been studied, including histamine administration to suppress MDSC-generated ROS [49], blockade of the CXCR2 chemokine receptor [50], and inhibition of CCRK (a cyclin-dependent kinase that promotes secretion o…”
Nishinakamura, H., Shinya, S., Irie, T., Sakihama, S., Naito, T., Watanabe, K., Sugiyama, D., Tamiya, M., Yoshida, T., Hase, T., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adk3160 · Cited by 16
Metastasis-promoting functions of myeloid cells
Kusmartsev, S. A. (2025) · Cancer and Metastasis Reviews · doi:10.1007/s10555-025-10278-y · Cited by 19
Classic versus innovative strategies for immuno-therapy in pancreatic cancer
Formelli, M. G., Palloni, A., Tavolari, S., Deiana, C., Andrini, E., Marco, M. D., Campana, D., Lamberti, G., & Brandi, G. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115671 · Cited by 16
Wong, S. W., McCarroll, J. A., Hsu, K., Geczy, C. L., & Tedla, N. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.826391 · Cited by 15
Co-dependencies in the tumor immune microenvironment
Chen, P., & Dey, P. (2022) · Oncogene · doi:10.1038/s41388-022-02406-7 · Cited by 15
“In Kras-mutated CRC [27], or p53-mutated rhabdomyosarcoma [110] mouse models, the anti-PD-1 therapy resistance is overcome by blocking MDSC infiltration via enforcing IRF2 expression or inhibition of CXCR2.”
BackgroundSarcoma Immunotherapy: Confronting Present Hurdles and Unveiling Upcoming Opportunities
Jeong, S., Afroz, S., Kang, D., Noh, J., Suh, J., Kim, J. H., You, H. J., Kang, H. G., Kim, Y., & Kim, J. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0079 · Cited by 16
“Highfill et al. (2014) showed that G-MDSCs could suppress T cells in rhabdomyosarcoma.”
Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future
Morel, V. J., Rössler, J. K., & Bernasconi, M. (2024) · Medicinal Research Reviews · doi:10.1002/med.22059 · Cited by 18
“102 Of note, in this model anti ‐ PD1 therapy prevented tumor growth if initiated early after tumor inoculation, whereas it had only limited benefit when administered later.”
Biomarkers for immune checkpoint therapy targeting programmed death 1 and programmed death ligand 1
Fan, J., Shen, X., Wang, Y., Zhou, H., Liu, G., Li, Y., & Xu, Z. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110621 · Cited by 15
Methylcholanthrene-Induced Sarcomas Develop Independently from NOX2-Derived ROS
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“In agreement with this and our results here (Fig 2), sarcomas have been shown to induce increases in circulating MDSC as shown in both humans and mice [24,35,36].”
ResultRegulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling
Piao, W., Wu, L., Xiong, Y., Zapas, G., Paluskievicz, C., Oakes, R. S., Pettit, S. M., Sleeth, M. L., Hippen, K. L., Schmitz, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54874-y · Cited by 14
“In addition to their chemotactic properties, CXCL1 is implicated in tumor growth, angiogenesis, and tumorigenesis 51 . ciLT also enhanced effector T cells and reduced MDSCs in TME, which may contribute to ef fi cient tumor regression at the early stage.”
InfluentialMyeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how
Zhai, Y., Liang, X., & Deng, M. (2024) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2024.06.04 · Cited by 14
Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis
Gong, R., Chen, Y., Chang, D. K.-F., Zhang, H., Liu, Z., & Yu, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1555036 · Cited by 14
Self-citationGao, P., Li, X., Duan, Z., Wang, Y., Li, Y., Wang, J., Luo, K., & Chen, J. (2025) · MedComm · doi:10.1002/mco2.70274 · Cited by 16
B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors
Jansen, L., Wienke, J., Molkenbur, R., Rössig, C., & Meissner, R. (2025) · Cancer and Metastasis Reviews · doi:10.1007/s10555-025-10294-y · Cited by 15
“MDSCs were found to be enriched also in pediatric solid cancers, along with both correlative and functional evidence in murine models of a key role in local immunosuppression [109–111].”
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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