Combinatorial Natural Killer Cell-based Immunotherapy Approaches Selectively Target Chordoma Cancer Stem Cells

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chordoma is a rare, recurrent, and metastatic tumor originating from notochord remnants.
• Cancer stem cells (CSCs) contribute to chordoma's resistance to conventional treatments.
• Targeting CSCs is a critical strategy for improving chordoma therapy.

Purpose of the Study:

• To evaluate the efficacy of NK cell-mediated immunotherapies against chordoma, with a focus on targeting CSCs.
• To investigate the synergistic effects of combining antibody-based therapies with NK cell activation.

Main Methods:

• Utilized in vitro cytotoxicity models to assess NK cell activity against chordoma cells.
• Tested the effects of anti-PD-L1 (N-601) and anti-EGFR (cetuximab) antibodies on NK cell-mediated lysis.
• Evaluated the impact of an IL-15 superagonist complex (N-803) and PD-L1-targeted CAR-NK cells (PD-L1 t-haNKs).
• Analyzed CSC vulnerability and expression of NK activating ligands (B7-H6, PD-L1) via flow cytometry.

Main Results:

• Anti-PD-L1 and anti-EGFR antibodies enhanced NK cell cytotoxicity against chordoma cells via ADCC.
• IL-15 superagonist (N-803) increased NK cell cytotoxicity, with further enhancement when combined with N-601 and/or cetuximab.
• PD-L1 t-haNKs demonstrated effectiveness against chordoma cells.
• CSCs were preferentially killed by NK cells when treated with N-601 and N-803.
• Chordoma CSCs express higher levels of B7-H6 and PD-L1 compared to non-CSCs.

Conclusions:

• Combinatorial NK cell-based immunotherapies show potential for effectively targeting chordoma.
• The enhanced targeting of CSCs suggests a promising therapeutic strategy for chordoma and other CSC-driven malignancies.
• Further clinical investigation of these NK cell-mediated approaches is warranted.