Product Citations: 2

Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation.
Using flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis.
In vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma.
To our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.
Copyright © 2024 Lopez, Fabian, Padget, Robbins, Kowalczyk, Lassoued, Pastor, Allen, Gallia, Gulley, Hodge and London.

  • Homo sapiens (Human)
  • Cancer Research
  • Immunology and Microbiology
  • Stem Cells and Developmental Biology

Despite the specificity and effectiveness of antibody therapy, resistance to treatment remains a major barrier for their broad clinical applications. While genetic mutations are known to be critical, the impact of non-genetic mechanisms, such as epigenetic changes and phenotypic adaptations, on resistance to antibody-dependent cellular cytotoxicity (ADCC) is not fully understood. Our study investigated the non-genetic resistance mechanisms that colorectal cancer cells develop against cetuximab and the resulting ADCC pressure. Resistance clones exhibited decreased EGFR/HER2 expressions, enriched interferon-related pathways, and lower NK cell activation. Interestingly, these resistance clones regained sensitivity upon the withdrawal of therapeutic pressure, implying phenotypic plasticity and reversibility. To counter resistance, we developed a mathematical model recapitulating the phenotypic switching dynamics. The model predicted that intermittent dosing strategy outperforms continuous regimen in delaying treatment resistance. Our findings have implications for improving efficacy and circumventing resistance to targeted antibody therapies.
© 2024 The Authors.

  • FC/FACS
  • Homo sapiens (Human)
  • Genetics
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