In brief

By boosting glycolysis and oxidative phosphorylation, IL-10 proteins trigger a metabolic shift in NK cells which increases their potency as cancer killers.

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Making the most of natural cancer killers

30 Nov 2022

A*STAR researchers discover a mechanism that fires up the metabolism of cancer-killing immune cells, paving the way for future cancer immunotherapies.

When pulling an all-nighter to meet an important deadline, there’s nothing like a cup of coffee for a much-needed boost of energy. Just like us, our immune cells work overtime too. Natural killer (NK) cells, for example, are on round-the-clock surveillance, looking to eliminate cancer or virus-infected cells. But how do these cells fuel themselves for all this hard work?

Deciphering the secrets of NK cell metabolism is a first step towards leveraging their power as cancer immunotherapies, said Kong-Peng Lam, Executive Director of A*STAR’s Singapore Immunology Network (SIgN).

“NK cell-based immunotherapy has several advantages over T cell therapies,” Lam explained. “They are safer and can be developed into off-the-shelf therapeutics to treat cancer patients.”

Work by Lam and Shengli Xu from SIgN aimed to advance previous studies that showed how immune cells process energy is tightly linked to their cancer-killing capabilities. The team focused on an immune-stimulating protein called interleukin (IL)-10, investigating its influence on NK cell metabolism in human cell-based assays.

The researchers discovered that contact with IL-10 turned the dial-up on two distinct metabolic pathways in NK cells—glycolysis and oxidative phosphorylation. Interestingly, this metabolic shift seemed to flip the switch on NK cells, turning them into potent cancer killers.

These results suggest that using IL-10 and other approaches to trigger this metabolic shift in NK cells could one day give patients the upper hand in their battle against cancer. However, scientists first need to figure out how to overcome the technical limitations of using live NK cells as cancer treatments in the clinic.

“Clinical-scale expansion of NK cells ex vivo is difficult,” explained Lam. “NK cells can also lose viability and activity during the freeze-thaw process.” Ongoing work by Lam and others in the field is helping to rise above these barriers, including developing strategies to maintain NK cell potency in the harsh, immune-suppressive tumour microenvironment.

The researchers remain spurred on by exciting results from experimental NK therapies in human trials. “Currently, there are many clinical trials on allogeneic NK or chimeric antigen receptor-transduced (CAR-NK) cells to treat patients with solid tumours, such as neuroblastoma, ovarian cancer, breast cancer and gastric cancer. Some of these have yielded promising results,” concluded Lam.

The A*STAR-affiliated researchers contributing to this research are from the Bioprocessing Technology Institute (BTI) and the Singapore Immunology Network (SIgN).

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Wang, Z., Gaun, D., Huo, J., Biswas, S.K., Huang, Y., et al. IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling, Frontiers in Immunology 12:619195 (2021) | article

About the Researchers

Kong-Peng Lam obtained his PhD in Immunology in 1994 from the College of Physicians & Surgeons at Columbia University, US. He then carried out postdoctoral research at the Institute for Genetics, University of Cologne, working to understand B cell biology and development. He is currently the Executive Director of A*STAR’s Singapore Immunology Network (SIgN), a Professor in the Departments of Microbiology and Immunology, Physiology, and Pediatrics at Yong Loo Lin School of Medicine, National University of Singapore (NUS), and an Adjunct Professor in the School of Biological Sciences at Nanyang Technological University (NTU).
Shengli Xu joined the Institute of Molecular and Cell Biology (IMCB), Singapore, beginning his PhD studies in 1998. Upon obtaining his PhD in Immunology in 2003, Xu pursued postdoctoral research, first as a Research Fellow at IMCB, and later as a Senior Research Fellow at Singapore Immunology Network (SIgN) until 2009. In 2009, he joined Bioprocessing Technology Institute (BTI) as a Research Scientist and progressed to become a Senior Lead Research Scientist and a Group Leader. In 2020, Xu rejoined SIgN as a Principal investigator to lead the B Cell Immunology Group. He is also an adjunction assistant professor at the Department of Physiology, NUS. Xu’s research primarily focuses on B-cell immunology and the development of antibody-based immunotherapy.

This article was made for A*STAR Research by Wildtype Media Group