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

J Exp Clin Cancer Res. 2024 Dec 5;43(1):318. doi: 10.1186/s13046-024-03240-3.

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.

Keywords: CXCR1; CXCR2; Docetaxel; HNSCC; IL-8; Immunotherapy.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Docetaxel* / administration & dosage
  • Docetaxel* / pharmacology
  • Drug Synergism
  • Female
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / immunology
  • Head and Neck Neoplasms* / pathology
  • Head and Neck Neoplasms* / virology
  • Humans
  • Mice
  • Papillomavirus Infections / drug therapy
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / virology
  • Receptors, Interleukin-8A* / antagonists & inhibitors
  • Receptors, Interleukin-8A* / metabolism
  • Receptors, Interleukin-8B* / antagonists & inhibitors
  • Receptors, Interleukin-8B* / metabolism
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Squamous Cell Carcinoma of Head and Neck / virology
  • Tumor Microenvironment* / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Docetaxel
  • Receptors, Interleukin-8B
  • Receptors, Interleukin-8A
  • CXCR2 protein, human