The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
A Novel Small Molecule Inhibitor of Signal Transducers and Activators of Transcription 3 Reverses Immune Tolerance in Malignant Glioma Patients
Abstract
Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients. [Cancer Res 2007;67(20):9630–6]
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Cites
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Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10
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The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions
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The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1
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Cited by
Targeting the IL-6/JAK/STAT3 signalling axis in cancer
Johnson, D. E., O'Keefe, R. A., & Grandis, J. R. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.8 · Cited by 3,110
Reactive Astrocytes: Production, Function, and Therapeutic Potential
Liddelow, S. A., & Barres, B. A. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.006 · Cited by 2,336
Tumor-associated macrophages: from basic research to clinical application
Yang, L., & Zhang, Y. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0430-2 · Cited by 847
Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas
Komohara, Y., Ohnishi, K., Kuratsu, J., & Takeya, M. (2008) · The Journal of Pathology · doi:10.1002/path.2370 · Cited by 738
Ouyang, S., Li, H., Lou, L., Huang, Q., Zhang, Z., Mo, J., Li, M., Lu, J., Zhu, K., Chu, Y., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102317 · Cited by 507
Metadata
- Authors
- Hussain, S. F., Kong, L.-Y., Jordan, J., Conrad, C., Madden, T., Fokt, I., Priebe, W., & Heimberger, A. B.
- Venue
- Cancer Research
- Published
- 2007-10-15
- Volume
- 67
- Issue
- 20
- Pages
- 9630-9636
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1965462445
- Cited by
- 314
- References
- 21
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- closed
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- Hussain, S. F., Kong, L.-Y., Jordan, J., Conrad, C., Madden, T., Fokt, I., Priebe, W., & Heimberger, A. B. (2007). A Novel Small Molecule Inhibitor of Signal Transducers and Activators of Transcription 3 Reverses Immune Tolerance in Malignant Glioma Patients. Cancer Research. https://doi.org/10.1158/0008-5472.can-07-1243
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