KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity.
Matthew D BluntSócrates Herrera ValenciaJack G FisherLara V GrahamAmber D P DoyleRebecca FultonMatthew J CarterMarta E PolakPeter W M JohnsonMark S CraggFrancesco ForconiSalim I KhakooPublished in: Journal of immunology (Baltimore, Md. : 1950) (2022)
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 KIR2DS2 high NK cells, and, accordingly, KIR2DS2 high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2 high 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.
Keyphrases
- nk cells
- single cell
- poor prognosis
- chronic lymphocytic leukemia
- rna seq
- induced apoptosis
- flow cytometry
- squamous cell carcinoma
- signaling pathway
- metabolic syndrome
- long non coding rna
- stem cells
- diffuse large b cell lymphoma
- bone marrow
- cell proliferation
- gene expression
- copy number
- endoplasmic reticulum stress
- weight loss
- glycemic control
- genome wide identification