CD25^bright NK cells display superior function and metabolic activity under regulatory T cell-mediated suppression

ABSTRACT

Infusion of natural killer (NK) cells is an attractive therapeutic modality in patients with cancer. However, the activity of NK cells is regulated by several mechanisms operating within solid tumors. Regulatory T (Treg) cells suppress NK cell activity through various mechanisms including deprivation of IL-2 via the IL-2 receptor alpha (CD25). Here, we investigate CD25 expression on NK cells to confer persistence in Treg cells containing solid tumor models of renal cell carcinoma (RCC). Compared with IL-2, stimulation with IL-15 increases the expression of CD25 resulting in enhanced response to IL-2 as evidenced by increased phosphorylation of STAT5. Compared with CD25^dim NK cells, CD25^bright NK cells isolated from IL-15 primed NK cells display increased proliferative and metabolic activity as well as increased ability to persist in Treg cells containing RCC tumor spheroids. These results support strategies to enrich for or selectively expand CD25^bright NK cells for adoptive cellular therapy of NK cells.

KEYWORDS:

• Natural killer cells
• regulatory T cells
• IL-15
• CD25
• tumor microenvironment

Acknowledgments

We thank Biomedicum Imaging Core (BIC). We thank Maria Johansson and Juan Basile at the Biomedicum Flow Cytometry Core Facility, Karolinska Institutet. We thank Weiyingqi Cui, Yi Chen, and Huaitao Cheng for their technical input.

Disclosure statement

The authors have no relevant competing interests to declare.

Data availability Statement

The data that support the findings of this study are available from the corresponding author, AL, upon reasonable request. Raw data of cellular fraction estimates, patient survival, and gene sets for scRNA-seq (GSE121638) were downloaded from https://gdc.cancer.gov, https://xenabrowser.net, and www.gsea-msigdb.org.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2175517

Additional information

Funding

This work was supported by the Cancer Research Funds of Radiumhemmet [181183, 211253]; The Swedish Cancer Society [CAN 2018/451, 21 1524 Pj].