Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy

Highfill, Steven L.; Cui, Yongzhi; Giles, Amber J.; Smith, Jillian P.; Zhang, Hua; Morse, Elizabeth; Kaplan, Rosandra N.; Mackall, Crystal L.

doi:10.1126/scitranslmed.3007974

Cited by 770Immune cells in cancerCancer Immunotherapy and BiomarkersChemokine receptors and signaling

Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy

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Highfill, Steven L., Cui, Yongzhi, Giles, Amber J., Smith, Jillian P., Zhang, Hua, Morse, Elizabeth, Kaplan, Rosandra N., Mackall, Crystal L.·2014·Science Translational Medicine

DOI 10.1126/scitranslmed.3007974PMC PMC6980372

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Abstract

Preventing trafficking of myeloid-derived suppressor cells to the tumor site enhances the efficiency of checkpoint blockade.

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Data from various mouse models indicate that disrupting the CXCR1/2-MDSC axis is therapeutically efficacious across a wide variety of solid cancers.
“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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Background
Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells
Henau, O. D., Rausch, M. P., Winkler, D. A., Campesato, L. F., Liu, C., Hirschhorn-Cymerman, D., Budhu, S., Ghosh, A., Pink, M. M., Tchaicha, J. H., et al. (2016) · Nature · doi:10.1038/nature20554 · Cited by 862 · see citing works
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
Steele, C. W., Karim, S. A., Leach, J. D. G., Bailey, P. J., Upstill‐Goddard, R., Rishi, L., Foth, M., Bryson, S., McDaid, K., Wilson, Z., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.014 · Cited by 850 · see citing works
“CXCR2 also regulates the migration of myeloid-derived suppressor cells (MDSCs) (Highfill et al., 2014).”
CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity
Teijeira, Á., Garasa, S., Gato, M., Alfaro, C., Miguéliz, I., Cirella, A., de Andrea, C., Ochoa, M. C., Otano, I., Etxeberría, I., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.03.001 · Cited by 799 · see citing works
Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases
Ha, H., Debnath, B., & Neamati, N. (2017) · Theranostics · doi:10.7150/thno.15625 · Cited by 788 · see citing works
“Inhibition of programmed death-1 (PD-1) by anti-PD-1 antibody prevented tumor growth during early phase tumor progression, but delayed treatment with anti-PD-1 therapy showed little benefits [346].”
Influential
Genetics and biology of prostate cancerPreprint
Wang, G., Zhao, D., Spring, D. J., & DePinho, R. A. (2018) · Genes & Development · doi:10.1101/gad.315739.118 · Cited by 761 · see citing works
Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?
Fares, C. M., Allen, E. M. V., Drake, C. G., Allison, J. P., & Hu‐Lieskovan, S. (2019) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_240837 · Cited by 648 · see citing works
Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches
Emran, T. B., Shahriar, A., Mahmud, A. R., Rahman, T., Abir, M. H., Siddiquee, M. F. R., Ahmed, H., Rahman, N., Nainu, F., Wahyudin, E., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891652 · Cited by 606 · see citing works
The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention
Cambier, S., Gouwy, M., & Proost, P. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-00974-6 · Cited by 605 · see citing works
“Moreover, CXCL8 induced the release of NETs in granulocytic MDSCs in vitro [108, 109].”
Background
Tumor microenvironment participates in metastasis of pancreatic cancer
Ren, B., Cui, M., Yang, G., Wang, H., Feng, M., You, L., & Zhao, Y. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0858-1 · Cited by 590 · see citing works
Resistance to PD1/PDL1 checkpoint inhibition
O’Donnell, J. S., Long, G. V., Scolyer, R. A., Teng, M. W. L., & Smyth, M. J. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.11.007 · Cited by 574 · see citing works
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics
Alshetaiwi, H. S., Pervolarakis, N., McIntyre, L. L., Ma, D., Nguyen, Q., Rath, J. A., Nee, K., Hernandez, G. A., Evans, K. T., Torosian, L., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.aay6017 · Cited by 521 · see citing works
Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine
Campesato, L. F., Budhu, S., Tchaicha, J. H., Weng, C., Gigoux, M., Cohen, I., Redmond, D., Mangarin, L. M. B., Pourpe, S., Liu, C., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17750-z · Cited by 536 · see citing works
Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome
Mira, J. C., Gentile, L. F., Mathias, B. J., Efron, P. A., Brakenridge, S. C., Mohr, A. M., Moore, F. A., & Moldawer, L. L. (2017) · Critical Care Medicine · doi:10.1097/ccm.0000000000002074 · Cited by 526 · see citing works
“Additionally, blockade of C-X-C motif chemokine receptor 2-mediated MDSC trafficking has been shown to enhance anti-programmed death 1 signaling efficacy in a murine model (79).”
Background
Genetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
“…that boosting dendritic cell function (Broz et al , 2014; Ruffell et al , 2014; Salmon et al , 2016; Sa ´ nchez-Paulete et al , 2016) or blocking myeloid cell-induced immunosuppression (Highfill et al , 2014; Zhu et al , 2014) improves the anti-tumor efficacy of immune checkpoint blockade.”
Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., et al. (2017) · Gut · doi:10.1136/gutjnl-2017-313738 · Cited by 495 · see citing works
Big opportunities for small molecules in immuno-oncology
Adams, J. L., Smothers, J. F., Srinivasan, R., & Hoos, A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4596 · Cited by 482 · see citing works
Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma
Chiu, D. K.-C., Tse, A. P.-W., Xu, I. M.-J., Di Cui, J., Lai, R. K.-H., Li, L. L., Koh, H.-Y., Tsang, F. H.-C., Wei, L. L., Wong, C.-M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00530-7 · Cited by 448 · see citing works
Classification of current anticancer immunotherapies
Galluzzi, L., Vacchelli, E., Pedro, J. M. B., Buqué, A., Senovilla, L., Baracco, E. E., Bloy, N., Castoldi, F., Abastado, J., Agostinis, P., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2998 · Cited by 471 · see citing works
“These include: (1) strategies for the depletion of circulating myeloid-derived suppressor cells (MDSCs), a bloodborne population of immature, immunosuppressive myeloid cells that generally accumulate in the course of tumor progression [513-516]; (2) mAbs that block CD47, one of the major antiphagocytic receptor expres…”
Background
Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy
Wu, Y., Yi, M., Niu, M., Mei, Q., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01657-y · Cited by 468 · see citing works
“Inhibition of CXCR2 has been shown to rescue MDSCs trafficking and enhance anti-PD-1 efficacy in murine glioblastoma and rhabdomyosarcoma [196, 197].”
Background
Neutrophils in cancer: prognostic role and therapeutic strategies
Ocaña, A., Nieto‐Jiménez, C., Pandiella, A., & Templeton, A. J. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0707-7 · Cited by 460 · see citing works
“Some studies have suggested an augmented effect when neutrophil targeting agents, CXCR2 inhibitors or anti-Ly6G, were combined with checkpoint inhibitors [46, 47].”
Background
Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
Zhang, Y., Chandra, V., Riquelme, E. M., Dutta, P., Quesada, P. R., Rakoski, A. I., Zoltan, M. A., Arora, N., Baydogan, S., Horne, W. T., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190354 · Cited by 447 · see citing works
Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors
Lei, Q., Wang, D., Sun, K., Wang, L., & Zhang, Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00672 · Cited by 414 · see citing works
Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer
Lin, C., He, H., Liu, H., Li, R., Chen, Y., Qi, Y., Jiang, Q., Chen, L., Zhang, P., Zhang, H., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-316324 · Cited by 420 · see citing works
Self-citation
Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer
Law, A. M. K., Valdes-Mora, F., & Gallego-Ortega, D. (2020) · Cells · doi:10.3390/cells9030561 · Cited by 455 · see citing works
Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)
Alfaro, C., Teijeira, A., Oñate, C., Pérez, G., Sanmamed, M. F., Andueza, M. P., Alignani, D., Labiano, S., Azpilikueta, A., Rodriguez-Paulete, A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2463 · Cited by 417 · see citing works
“However, our results further argue in favor of the convenience of pharmacologically inhibiting IL-8 as previously carried out in xenografted mouse models and currently in clinical trials with neutralizing antibodies (51) and small drug inhibitors (52).”
Result
Immunosuppressive cells in tumor immune escape and metastasis
Liu, Y., & Cao, X. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1376-x · Cited by 401 · see citing works
Mechanisms of Resistance to PD-1 and PD-L1 Blockade
Nowicki, T. S., Hu‐Lieskovan, S., & Ribas, A. (2018) · The Cancer Journal · doi:10.1097/ppo.0000000000000303 · Cited by 398 · see citing works
“Several studies have demonstrated that depletion of intratumorMDSCs restores the effectiveness of PD-1 blockade.(78,79) Another immunosuppressive cell type within the TME is the regulatory T (Treg) cell.”
Lessons learned from the blockade of immune checkpoints in cancer immunotherapy
Li, X., Shao, C., Shi, Y., & Han, W. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0578-4 · Cited by 385 · see citing works
“Growing evidence also suggest that heavy tumor infiltration by MDSCs correlated with poor prognosis and decreased efficacy of immunotherapies, including ICB therapy [74], adoptive T cell therapy (ACT) [75], and DCs vaccines [76].”
Background
Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy
Vilgelm, A. E., & Richmond, A. J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00333 · Cited by 372 · see citing works
Interleukin-8 in cancer pathogenesis, treatment and follow-up
Alfaro, C., Sanmamed, M. F., Rodriguez-Ruiz, M. E., Teijeira, Á., Oñate, C., González, Á., Ponz‐Sarvisé, M., Schalper, K. A., Perez‐Gracia, J. L., & Melero, I. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.08.004 · Cited by 373 · see citing works
Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma
Loeuillard, E. J., Yang, J., Buckarma, E. H., Wang, J., Liu, Y., Conboy, C. B., Pavelko, K. D., Li, Y., O’Brien, D. R., Wang, C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137110 · Cited by 370 · see citing works
“MDSCs also have a significant association with poor patient outcomes as well as chemotherapy and immunotherapy resistance (35, 47).”
Background
Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age?
Hou, J., Karin, M., & Sun, B. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00459-9 · Cited by 376 · see citing works
Immunosuppression associated with chronic inflammation in the tumor microenvironment
Wang, D., & DuBois, R. N. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv123 · Cited by 358 · see citing works
“However, recent in vivo studies showed that inhibition of tumor-infiltrating MDSCs by targeting CXCR2 enhanced antiPD-1 efficacy in rhabdomyosarcoma in vivo (125) and improved the efficacy of chemotherapy in a spontaneous mouse model of prostate cancer (71).”
Background
Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition
Taki, M., Abiko, K., Ukita, M., Murakami, R., Yamanoi, K., Yamaguchi, K. D., Hamanishi, J., Baba, T., Matsumura, N., & Mandai, M. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-4459 · Cited by 357 · see citing works
Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases
Cheng, Y., Ma, X., Wei, Y.-Q., & Wei, X. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.01.005 · Cited by 343 · see citing works
Neutrophil phenotypes and functions in cancer: A consensus statement
Quail, D. F., Amulic, B., Aziz, M., Barnes, B. J., Eruslanov, E. B., Fridlender, Z. G., Goodridge, H. S., Granot, Z., Hidalgo, A., Huttenlocher, A., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220011 · Cited by 336 · see citing works
“In preclinical models of childhood cancers such as rhabdomyosarcoma, CXCR2+Ly6G+ cells mediate local immunosuppression, while CXCR2 inhibition improves immune checkpoint blockade efficacy (Highfill et al., 2014).”
Background
NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps
Adrover, J. M., McDowell, S. A. C., He, X., Quail, D. F., & Egeblad, M. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.001 · Cited by 349 · see citing works
Tumor microenvironment in gastric cancers
Oya, Y., Hayakawa, Y., & Koike, K. (2020) · Cancer Science · doi:10.1111/cas.14521 · Cited by 332 · see citing works
Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors
Merchant, M. S., Wright, M., Baird, K., Wexler, L. H., Rodriguez-Galindo, C., Bernstein, D., Delbrook, C., Lodish, M., Bishop, R., Wolchok, J. D., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0491 · Cited by 331 · see citing works
“, MDSC, Treg) so that effective immune checkpoint therapy may require combination therapies for maximal impact (25, 32).”
BackgroundSelf-citation
Epigenetic therapy inhibits metastases by disrupting premetastatic niches
Lu, Z., Zou, J., Li, S., Topper, M. J., Tao, Y., Zhang, H., Jiao, X., Xie, W., Kong, X., Vaz, M., et al. (2020) · Nature · doi:10.1038/s41586-020-2054-x · Cited by 330 · see citing works
Self-citation
Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas
Long, A. H., Highfill, S. L., Cui, Y., Smith, J. P., Walker, A. J., Ramakrishna, S., El-Etriby, R., Galli, S., Tsokos, M. G., Orentas, R. J., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0230 · Cited by 329 · see citing works
“Granulocytic MDSCs are a primary mediator of immune evasion in murine models of sarcoma (30), so we examined whether similar MDSCs were contributing to an immunosuppressive microenvironment that inhibits in vivo efficacy of GD2-CAR T cells against sarcomas.”
BackgroundInfluentialSelf-citation
Emerging Opportunities and Challenges in Cancer Immunotherapy
Whiteside, T. L., Demaria, S., Rodriguez-Ruiz, M. E., Zarour, H. M., & Melero, I. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0049 · Cited by 318 · see citing works
“Not surprisingly, MDSC accumulation in tumors appears to interfere with anti–PD-1 immunotherapy, and targeting of CXCR2þ MDSC with antibodies was reported to improve the efficiency of the checkpoint blockade (44).”
Background
The Role of Tumor-Associated Neutrophils in Colorectal Cancer
Mizuno, R., Kawada, K., Itatani, Y., Ogawa, R., Kiyasu, Y., & Sakai, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030529 · Cited by 318 · see citing works
Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy
Ren, D., Hua, Y., Yu, B., Ye, X., He, Z., Li, C., Wang, J., Mo, Y., Wei, X., Chen, Y., et al. (2020) · Molecular Cancer · doi:10.1186/s12943-020-1144-6 · Cited by 318 · see citing works
“In children with metastatic sarcoma, the efficacy of PD-1 blockade therapy was significantly improved by treatment with an anti-CXCR2 monoclonal antibody [168].”
Background
Tumor-associated neutrophils and neutrophil-targeted cancer therapies
Que, H., Fu, Q., Lan, T., Tian, X., & Wei, X. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188762 · Cited by 319 · see citing works
Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment
Ruffin, A., Li, H., Vujanović, L., Zandberg, D., Ferris, R., & Bruno, T. (2022) · Nature Reviews. Cancer · doi:10.1038/s41568-022-00531-9 · Cited by 293 · see citing works
Human neutrophils: Their role in cancer and relation to myeloid-derived suppressor cells
Moses, K., & Brandau, S. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.03.018 · Cited by 306 · see citing works
Therapeutic targeting of tumour myeloid cells
Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D., & Morton, J. P. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00546-2 · Cited by 305 · see citing works
Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6Clow F4/80+ Extratumoral Macrophages
Beatty, G. L., Winograd, R., Evans, R. A., Long, K. B., Luque, S. L., Lee, J. W., Clendenin, C. J., Gladney, W. L., Knoblock, D. M., Guirnalda, P. D., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.010 · Cited by 293 · see citing works
Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook
Horvath, L., Thienpont, B., Zhao, L., Wolf, D. G. F., & Pircher, A. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01260-z · Cited by 286 · see citing works
Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity
Ring, N. G., Herndler‐Brandstetter, D., Weiskopf, K., Shan, L., Volkmer, J.-P., George, B. M., Lietzenmayer, M., McKenna, K. M., Naik, T. J., McCarty, A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710877114 · Cited by 281 · see citing works
Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy
Shi, L., Wang, J., Ding, N., Zhang, Y., Zhu, Y., Dong, S., Wang, X., Peng, C., Zhou, C., Zhou, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13204-3 · Cited by 283 · see citing works
CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer
Zhang, H., Ye, Y. L., Li, M.-X., Ye, S.-B., Huang, W.-R., Cai, T.-T., He, J., Peng, J.-Y., Duan, T., Cui, J., et al. (2016) · Oncogene · doi:10.1038/onc.2016.367 · Cited by 279 · see citing works
Self-citation
Targeting m 6 A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer
Bao, Y., Zhai, J., Chen, H., Wong, C. C., Liang, C., Ding, Y., Huang, D., Gou, H., Chen, D., Pan, Y., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-328845 · Cited by 278 · see citing works
“Considering that reduced infiltration of MDSCs has been reported to correlate with enhanced immunotherapeutic efficacy in various cancer types, 22 29 30 we sought to test if targeting YTHDF1 augments anti-PD1 therapy in CRC.”
Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors
Bilušić, M., Heery, C. R., Collins, J. M., Donahue, R. N., Palena, C., Madan, R. A., Karzai, F. H., Marté, J. L., Strauss, J., Gatti-Mays, M. E., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0706-x · Cited by 274 · see citing works
IL8, Neutrophils, and NETs in a Collusion against Cancer Immunity and Immunotherapy
Teijeira, Á., Garasa, S., Ochoa, M. C., Villalba-Esparza, M., Olivera, I., Cirella, A., Eguren‐Santamaría, I., Berraondo, P., Schalper, K. A., de Andrea, C. E., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1319 · Cited by 270 · see citing works
“11), and neutrophils, withmajor implications for antitumor immunity (12).”
Background
Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade
Conche, C., Finkelmeier, F., Pesic, M. H., Nicolas, A. M., Böttger, T. W., Kennel, K. B., Denk, D., Ceteci, F., Mohs, K., Engel, E., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-327909 · Cited by 267 · see citing works
Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer
Li, L., Wang, L., Li, J., Fan, Z., Li, Y., Zhang, Z., Zhang, C., Yue, D., Qin, G., Zhang, T., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2460 · Cited by 266 · see citing works
“Depletion of MDSCs or inhibiting MDSCs function mitigates cancer progression (52, 53).”
Background
Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer
Li, S., Yu, W., Xie, F., Luo, H., Liu, Z., Lv, W., Shi, D., Yu, D., Gao, P., Chen, C., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35431-x · Cited by 263 · see citing works
Cancer Stemness Meets Immunity: From Mechanism to Therapy
Chen, P., Hsu, W., Han, J., Xia, Y., & DePinho, R. A. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108597 · Cited by 251 · see citing works
A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy
Theivanthiran, B., Evans, K. S., DeVito, N. C., Plebanek, M. P., Sturdivant, M., Wachsmuth, L. P., Salama, A. K. S., Kang, Y., Hsu, D. S., Balko, J. M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133055 · Cited by 251 · see citing works
“Additional work has shown that CXCR2 blockade enhances the efficacy of anti-PD-1 ab immunotherapy in models of both pancreatic cancer and sarcoma (8-10).”
Background
Clinical cancer immunotherapy: Current progress and prospects
Liu, C., Yang, M., Zhang, D., Chen, M., & Zhu, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.961805 · Cited by 249 · see citing works
CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma
Chao, T., Furth, E. E., & Vonderheide, R. H. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0188 · Cited by 248 · see citing works
“CXCR2 is also essential for the recruitment of TANs in various cancers (32, 33).”
BackgroundResult
Nitric Oxide Production by Myeloid Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function.
Stiff, A., Trikha, P., Mundy-Bosse, B., McMichael, E., Mace, T. A., Benner, B., Kendra, K., Campbell, A., Gautam, S., Abood, D., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0691 · Cited by 244 · see citing works
“The presence of immunosuppressive cells like MDSCs in the tumormicroenvironment canbe amajor impediment to immunebased therapies (53).”
Background
Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy
Sun, L., Clavijo, P. E., Robbins, Y. L., Patel, P., Friedman, J., Greene, S., Das, R., Silvin, C., Waes, C. V., Horn, L. A., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126853 · Cited by 240 · see citing works
“CXCR2 blockade using a commercially available anti–mouse CXCR2 mAb (12).”
Method
The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2
Hartwig, T., Montinaro, A., von Karstedt, S., Sevko, A., Šurinová, S., Chakravarthy, A., Taraborrelli, L., Dráber, P., Lafont, É., Vargas, F. A., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.021 · Cited by 234 · see citing works
“GR1+ cells (Highfill et al., 2014; Toh et al., 2011), we compared myeloid immune cell infiltration in the microenvironment of FADD-proficient and FADD-deficient tumors.”
Background
CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target
Zhang, W., Wang, H., Sun, M., Deng, X., Wu, X., Ma, Y., Li, M., Shuoa, S. M., You, Q., & Miao, L. (2020) · 癌症：英文版 · doi:10.1002/cac2.12010 · Cited by 239 · see citing works
Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology
Jiao, X., Nawab, O., Patel, T. A., Kossenkov, A. V., Halama, N., Jaeger, D., & Pestell, R. G. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1167 · Cited by 232 · see citing works
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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.
ORCID: Highfill, Steven L.
Cui, Yongzhi
Giles, Amber J.
Zhang, Hua
Kaplan, Rosandra N.
Mackall, Crystal L.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2014-05-21
Volume: 6
Issue: 237
Pages: 237ra67-237ra67
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.3007974
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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Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy

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