A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer

Mol Ther. 2021 Oct 6;29(10):2963-2978. doi: 10.1016/j.ymthe.2021.05.014. Epub 2021 May 21.

Abstract

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease.

Keywords: SDF-1/CXCR4 axis; chemotherapy; combination therapy; inflammatory monocytes; lung cancer stem cells; metastasis; peptide anti-CXCR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • AC133 Antigen / metabolism*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Chemokine CXCL12 / metabolism*
  • Cisplatin / administration & dosage*
  • Cisplatin / pharmacology
  • Drug Interactions
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Male
  • Mice
  • Monocytes / metabolism*
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / immunology
  • Peptides / administration & dosage*
  • Peptides / pharmacology
  • RAW 264.7 Cells
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • AC133 Antigen
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • PROM1 protein, human
  • Peptides
  • Receptors, CXCR4
  • Cisplatin