KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity
Matthew D Blunt1, Andres Vallejo Pulido2, Jack G Fisher2
1School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom; and m.d.blunt@soton.ac.uk.
Abstract:
NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell-mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.
Insights
Killer cell Ig-like receptors (KIRs) like KIR2DS2 enhance natural killer (NK) cell anticancer activity. This research shows KIR2DS2 marks NK cells primed for improved cancer immunotherapy outcomes.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Therapeutics
Background:
- Natural killer (NK) cells are crucial for cancer immunity.
- Activating killer cell Ig-like receptors (KIRs) influence NK cell function and cancer outcomes.
- KIR2DS2 shows promise in hematological and solid tumors, but its mechanism is unclear.
Purpose of the Study:
- To investigate the impact of KIR2DS2 expression on NK cell function.
- To elucidate the mechanisms underlying KIR2DS2's association with improved cancer outcomes.
- To identify KIR2DS2 as a potential target for NK cell-based cancer therapies.
Main Methods:
- Novel flow cytometry panel to analyze KIR2DS2 expression on NK cells.
- Assessment of NK cell activation against various cancer cell lines and primary leukemia cells.
- Bulk and single-cell RNA sequencing to identify molecular pathways associated with KIR2DS2 expression.
Main Results:
- High KIR2DS2 expression correlates with enhanced spontaneous NK cell activation against B cell lines, liver cancer, and chronic lymphocytic leukemia.
- KIR2DS2high NK cells exhibit increased CD16 expression and augmented antibody-dependent cellular cytotoxicity (ADCC).
- RNA sequencing reveals upregulation of cytotoxicity, translation, and FCGR pathways in KIR2DS2high NK cells.
Conclusions:
- KIR2DS2 marks a subset of NK cells with heightened anticancer activity.
- KIR2DS2 expression is linked to enhanced NK cell cytotoxicity and response to antibody-based therapies.
- KIR2DS2 represents a promising target for developing novel NK cell-based cancer immunotherapies.
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