Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models
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Abstract
Purpose: Natural killer (NK)-cell–based immunotherapy may overcome obstacles to effective T-cell–based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC. Experimental Design: The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell–inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells. Results: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide. Conclusions: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
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SX-682 is predicted to unmask greater efficacy of chemotherapy and immunotherapies whose mechanisms are non-redundant and complementary to CXCR1/2 antagonism.
“By reversing MDSC-mediated immunosuppression, SX-682 is also predicted to unmask greater efficacy of chemotherapy and immunotherapies (such as anti-CTLA4 and anti-PD-1 antibodies) that act by mechanisms that are non-redundant and indeed complementary to those of CXCR1/2 antagonists173.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [173]
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- Authors
- Greene, S., Robbins, Y., Mydlarz, W. K., Huynh, A. P., Schmitt, N. C., Friedman, J., Horn, L. A., Palena, C., Schlom, J., Maeda, D. Y., Zebala, J. A., Clavijo, P. E., & Allen, C.
- Affiliations
- National Institutes of Health (US)
- National Institute on Deafness and Other Communication Disorders (US)
- Johns Hopkins University (US)
- National Cancer Institute (US)
- 5Syntrix Pharmaceuticals, Auburn, Washington.
- 1Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-03-13
- Volume
- 26
- Issue
- 6
- Pages
- 1420-1431
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7073293
- OpenAlex
- W2995367800
- Cited by
- 280
- References
- 30
- Citations by year
- 2026: 31 · 2025: 44 · 2024: 57 · 2023: 52 · 2022: 42 · 2021: 40 · 2020: 14
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Deafness and Other Communication Disorders (ZIA-DC000087)
- DDCF (2014194)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- myeloid-derived suppressor cells, head and neck squamous cell carcinoma, adoptive NK cell transfer, tumor immunosuppression, TGF-beta, nitric oxide, monocytic MDSCs, tumor microenvironment
- MeSH terms
- Myeloid-Derived Suppressor Cells, Antineoplastic Agents, Immunological, Animals, Disease Models, Animal, Head and Neck Neoplasms, Humans, Immunotherapy, Killer Cells, Natural, Leukocytes, Mononuclear, Mice, Inbred C57BL, Mouth Neoplasms, Transforming Growth Factor beta, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Cell Line, Tumor, Mice, Tumor Microenvironment
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