Investigators have discovered that targeting specific mechanisms linked to lipid metabolism in immune cells within tumors may improve response to current and future cancer immunotherapies, according to a recent study published in the journal Immunity.
“This paper provides additional evidence that suggests how lipid metabolism plays an important role intrinsically in the CD8+ T-cell compartment, particularly in the tumor microenvironment, and especially in the context of checkpoint blockade therapy,” said Bin Zhang, MD, PhD, the Johanna Dobe Professor of Cancer Immunology and a co-author of the study.
Phospholipid metabolism, or the regulation of lipids to support cell growth and proliferation, is a fundamental metabolic mechanism that can impact how the body’s immune system responds to different pathogens, including cancer.
In the current study, Zhang and his team aimed to determine the impact of the tumor microenvironment on phospholipid metabolism in adaptive immune cells called CD8+ T-cells, which are known to play a key role in tumor surveillance and defense.
Using advanced cellular techniques, the scientists studied peripheral blood mononuclear cells (PBMCs), circulating immune cells found in the blood, and tumor tissue samples from five patients with lung cancer.
From these samples, the investigators found that phospholipid levels were lower in intratumoral CD8+ T-cells than in circulating CD8+ T-cells. Notably, intratumoral CD8+ T-cells showed decreased expression of the phospholipid phosphatase 1 enzyme (PLPP1), which accelerates phospholipid synthesis.
Using genome editing to delete PLPP1 from these CD8+ T-cells impaired antitumor immunity and promoted T-cell death through ferroptosis, a newly discovered type of cell death that is dependent on iron accumulation and lipid peroxidation, which results in oxidative stress. Furthermore, the investigators found that PD-1 (programmed death-1) signaling – a known regulator of immune system function – in CD8+ T-cells ultimately suppressed PLPP1 expression.
The findings suggest that PD-1 signaling regulates phospholipid metabolism in CD8+ T-cells, which has implications for improving patient response to current immunotherapies and informing the development of new therapeutic strategies.
“I think increasing this molecule, PLPP1, in CD8+ T-cells may be the key to allow these T-cells to better respond to checkpoint blockade therapy,” said Zhang, who is also a professor of Medicine in the Division of Hematology and Oncology, of Microbiology-Immunology and of Pathology. “We still have lots of questions in terms of translational potential, but this seems like a very attractive target.”
Zhang is also a co-leader of the Tumor Environment and Metastasis Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a member of the Center for Human Immunobiology.
This work was supported by the National Key R&D Program: Intergovernmental International Science and Technology Innovation Cooperation Project (grant 2022YFE0141000), the National Natural Science Foundation of China (grants 82102869, 82001659, and 82272873), the Central Government of Henan Province Guides Local Science and Technology Development Fund Projects (grant Z20221343036), the Medical Science and Technology Project of Henan Province (grants SBGJ202103083 and SBGJ202101010), the Innovation Team Project within the First Affiliated Hospital of Zhengzhou University (grant QNCXTD2023010), and the Major Public Welfare Projects in Henan Province (grant 201300310400).
