Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models
Abstract Background Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade...
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| Language: | English |
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BMC
2024-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03240-3 |
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| author | Lucas A. Horn Hanne Lind Kristen Fousek Haiyan Qin Nika Rajabian Shantel Angstadt Nicole Hsiao-Sanchez Miriam M. Medina-Enriquez Marcus D. Kelly Clint T. Allen Sarah M. Hammoudeh Roberto Weigert Dean Y. Maeda John A. Zebala Claudia Palena |
| author_facet | Lucas A. Horn Hanne Lind Kristen Fousek Haiyan Qin Nika Rajabian Shantel Angstadt Nicole Hsiao-Sanchez Miriam M. Medina-Enriquez Marcus D. Kelly Clint T. Allen Sarah M. Hammoudeh Roberto Weigert Dean Y. Maeda John A. Zebala Claudia Palena |
| author_sort | Lucas A. Horn |
| collection | DOAJ |
| description | Abstract Background Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC. Methods Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel. Results High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8+ T cells in the combination therapy treated tumors compared to controls. Conclusions This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies. |
| format | Article |
| id | doaj-art-66927b8d4cfe4aeca811e4aff6bc75e1 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-66927b8d4cfe4aeca811e4aff6bc75e12025-08-20T02:31:00ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-12-0143112210.1186/s13046-024-03240-3Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer modelsLucas A. Horn0Hanne Lind1Kristen Fousek2Haiyan Qin3Nika Rajabian4Shantel Angstadt5Nicole Hsiao-Sanchez6Miriam M. Medina-Enriquez7Marcus D. Kelly8Clint T. Allen9Sarah M. Hammoudeh10Roberto Weigert11Dean Y. Maeda12John A. Zebala13Claudia Palena14Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSurgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSyntrix PharmaceuticalsSyntrix PharmaceuticalsCenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract Background Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC. Methods Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel. Results High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8+ T cells in the combination therapy treated tumors compared to controls. Conclusions This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.https://doi.org/10.1186/s13046-024-03240-3HNSCCCXCR1CXCR2IL-8DocetaxelImmunotherapy |
| spellingShingle | Lucas A. Horn Hanne Lind Kristen Fousek Haiyan Qin Nika Rajabian Shantel Angstadt Nicole Hsiao-Sanchez Miriam M. Medina-Enriquez Marcus D. Kelly Clint T. Allen Sarah M. Hammoudeh Roberto Weigert Dean Y. Maeda John A. Zebala Claudia Palena Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models Journal of Experimental & Clinical Cancer Research HNSCC CXCR1 CXCR2 IL-8 Docetaxel Immunotherapy |
| title | Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models |
| title_full | Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models |
| title_fullStr | Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models |
| title_full_unstemmed | Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models |
| title_short | Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models |
| title_sort | inhibition of the chemokine receptors cxcr1 and cxcr2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of hpv negative head and neck cancer models |
| topic | HNSCC CXCR1 CXCR2 IL-8 Docetaxel Immunotherapy |
| url | https://doi.org/10.1186/s13046-024-03240-3 |
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