Analysis of Phenotypic and Molecular Variability of Memory-like NK Cells for Cancer Adoptive Cell Therapy Screening

TL;DR

This study examines how memory-like NK cells vary in function and metabolism, highlighting the need to screen for the best cell products for cancer immunotherapy.

Contribution

The study identifies metabolic and functional variability in memory-like NK cells for cancer adoptive cell therapy screening.

Findings

Memory-like NK cells show significant differences in cytotoxicity against head and neck cancer cells.

Poor cytotoxicity correlates with weak motility and disrupted metabolic gene expression.

Blocking glycolysis and OXPHOS impairs memory-like NK cell function, emphasizing the role of metabolism.

Abstract

Adoptive cell therapy has emerged as an alternative cancer immunotherapeutic option. Memory-like natural killer (NK) cells are a type of immune cell that have shown promise due to their superior ability to persist in vivo after cytokine preactivation and exhibit a robust response upon antigen re-exposure. However, memory-like NK cells can vary in quality based on their functional and molecular characteristics. In this study, we studied functional heterogeneity across memory-like NK cell products generated from multiple donors. We observed that there were significant differences across several parameters for these NK cell products, most notably in their cytotoxic (killing) capacity against head and neck cancer cells. Memory-like NK cells that exhibited poor cytotoxicity also had the weakest motility and disrupted gene expression related to metabolism. Overall, our findings underscore the importance of characterizing memory-like NK cells to identify the most effective donor-derived products for adoptive cell therapy of cancer.

Background: Adoptive cell therapies are emerging as a promising therapeutic option against hematological and solid malignancies. Memory-like natural killer (mlNK) cells are a specific subtype of NK cells generated after cytokine preactivation that have shown enhanced in vivo persistence after infusion into patients, an issue that has hindered traditional NK cell immunotherapy. However, the quality and variability of mlNK cell products remains poorly defined. Methods: In this study, we evaluated heterogeneity across critical functional and molecular aspects of mlNK cells generated from independent donors, including mlNK cytotoxicity, cluster formation, motility, mitochondria morphology, and gene expression. Results: We observed a correlation between changes in gene expression associated with glycolysis and key NK cell functions such as cytotoxicity and motility. For further characterization, we blocked glycolysis and oxidative phosphorylation (OXPHOS) and observed an impaired mlNK functional response, suggesting the importance of metabolism. Conclusions: Our findings provide insights into discriminating between mlNK cell products and how the predictive markers can identify optimal mlNK cell products for adoptive cell therapy of cancer.

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