Zhang Yi's Team Discovers the Role of Phospholipid Phosphatase PLPP1 in Regulating the Anti-tumor Function of Tumor-Infiltrating CD8 T Cells
Source：Zhang Yi
2024-09-27
Cell metabolism plays a pivotal role in cancer immune responses. Changes in glucose, lipid, and amino acid metabolism within tumors can affect the anti-tumor activity of immune cells and promote tumor progression. Lipid metabolism not only regulates signal transduction but also provides energy for cells, influencing multiple aspects of immune responses. The activation, proliferation, and cytokine secretion of CD8+ T cells under tumor antigen stimulation are all influenced by lipid metabolism. The tumor microenvironment is a complex and disturbed metabolic environment, and tumor-infiltrating CD8+ T cells exhibit abnormal lipid metabolism.
On August 28, 2024, Professor Zhang Yi's team from the biotherapy center of the First Affiliated Hospital of Zhengzhou University published a research paper titled "PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis" in the journal Immunity. This study reveals the crucial role of phospholipid metabolism in regulating the anti-tumor function of tumor-infiltrating CD8+ T cells, clarifying that PLPP1-mediated phospholipid metabolism in tumor-infiltrating CD8+ T cells helps T cells resist ferroptosis, thereby enhancing their anti-tumor function and its significance in immunotherapy.
Phospholipids are one of the most abundant metabolites in cells and play an important role in immune responses. Phosphatidylethanolamine plays a key role in the differentiation of T cell helper cells, while sphingomyelin is crucial for maintaining the anti-tumor function of natural killer cells within tumors. However, the lipid metabolism of tumor-infiltrating CD8+ T cells remains unclear. This study aimed to explore the impact of phospholipid metabolism on the anti-tumor function of tumor-infiltrating CD8+ T cells. Through mass spectrometry analysis, Professor Zhang Yi's team discovered that the phospholipid metabolism regulated by phospholipid phosphatase 1 (PLPP1) in tumor-infiltrating CD8+ T cells was impaired. The authors assessed the correlation between PLPP1 expression and the anti-tumor activity of CD8+ T cells, initially finding that PLPP1 expression was decreased in tumor-infiltrating CD8+ T cells, and that PLPP1 expression was positively correlated with genes related to the anti-tumor function of CD8+ T cells.
To investigate the effect of PLPP1 on the anti-tumor function of CD8+ T cells, the authors constructed a mouse model with specific knockout of PLPP1 in T cells. They found that PLPP1-knockout tumor-infiltrating CD8+ T cells underwent significant ferroptosis, characterized by increased intracellular reactive oxygen species, increased peroxidized lipids, damaged mitochondrial structures, and increased intracellular unsaturated phospholipids. The authors also discovered that the accumulation of unsaturated fatty acids in tumors was the main contributor to ferroptosis in PLPP1-deficient CD8+ T cells.
Anti-PD-1 therapy has made significant progress in tumor treatment, restoring the proliferation, survival, and function of CD8+ T cells. However, research on metabolic changes in CD8+ T cells after anti-PD-1 treatment remains limited. Professor Zhang Yi's team discovered that the reduction of PLPP1 in CD8+ T cells was associated with the activation of the PD-1 signaling pathway. PD-1 pathway activation inhibited PLPP1-mediated lipid metabolism, providing a novel perspective for understanding immunotherapy. Furthermore, based on RNA sequencing data analysis, the authors found that PLPP1 expression levels were positively correlated with the genetic characteristics of responders to anti-PD-1 treatment, suggesting that PLPP1 may be a key metabolic target for improving the anti-tumor function of T cells.
Professor Zhang Yi's team's research work, for the first time, reveals the important relationship between PLPP1 and the anti-tumor function of CD8+ T cells and discovers that the activation of PD-1 signaling inhibits PLPP1 expression in CD8+ T cells. This research clarifies that PLPP1 can serve as a regulator of tumor-infiltrating CD8+ T cell function, which is conducive to improving the efficacy of immunotherapy. Additionally, the discovery that overexpression of PLPP1 can enhance the anti-tumor function of CAR-T cells provides a new research target for genetically engineered T cell modification.
Professor Zhang Yi from the biotherapy center of the First Affiliated Hospital of Zhengzhou University is the corresponding author of this paper. Assistant Researcher Ping Yu, Resident Physician Shan Jiqi, and PhD student Qin Hainam are the first authors. The research project was supported by the National Key R&D Program of China, the National Natural Science Foundation of China and Science and Technology Department of Henan Province.
Article Links: https://www.sciencedirect.com/science/article/pii/S1074761324003765
On August 28, 2024, Professor Zhang Yi's team from the biotherapy center of the First Affiliated Hospital of Zhengzhou University published a research paper titled "PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis" in the journal Immunity. This study reveals the crucial role of phospholipid metabolism in regulating the anti-tumor function of tumor-infiltrating CD8+ T cells, clarifying that PLPP1-mediated phospholipid metabolism in tumor-infiltrating CD8+ T cells helps T cells resist ferroptosis, thereby enhancing their anti-tumor function and its significance in immunotherapy.
Phospholipids are one of the most abundant metabolites in cells and play an important role in immune responses. Phosphatidylethanolamine plays a key role in the differentiation of T cell helper cells, while sphingomyelin is crucial for maintaining the anti-tumor function of natural killer cells within tumors. However, the lipid metabolism of tumor-infiltrating CD8+ T cells remains unclear. This study aimed to explore the impact of phospholipid metabolism on the anti-tumor function of tumor-infiltrating CD8+ T cells. Through mass spectrometry analysis, Professor Zhang Yi's team discovered that the phospholipid metabolism regulated by phospholipid phosphatase 1 (PLPP1) in tumor-infiltrating CD8+ T cells was impaired. The authors assessed the correlation between PLPP1 expression and the anti-tumor activity of CD8+ T cells, initially finding that PLPP1 expression was decreased in tumor-infiltrating CD8+ T cells, and that PLPP1 expression was positively correlated with genes related to the anti-tumor function of CD8+ T cells.
To investigate the effect of PLPP1 on the anti-tumor function of CD8+ T cells, the authors constructed a mouse model with specific knockout of PLPP1 in T cells. They found that PLPP1-knockout tumor-infiltrating CD8+ T cells underwent significant ferroptosis, characterized by increased intracellular reactive oxygen species, increased peroxidized lipids, damaged mitochondrial structures, and increased intracellular unsaturated phospholipids. The authors also discovered that the accumulation of unsaturated fatty acids in tumors was the main contributor to ferroptosis in PLPP1-deficient CD8+ T cells.
Anti-PD-1 therapy has made significant progress in tumor treatment, restoring the proliferation, survival, and function of CD8+ T cells. However, research on metabolic changes in CD8+ T cells after anti-PD-1 treatment remains limited. Professor Zhang Yi's team discovered that the reduction of PLPP1 in CD8+ T cells was associated with the activation of the PD-1 signaling pathway. PD-1 pathway activation inhibited PLPP1-mediated lipid metabolism, providing a novel perspective for understanding immunotherapy. Furthermore, based on RNA sequencing data analysis, the authors found that PLPP1 expression levels were positively correlated with the genetic characteristics of responders to anti-PD-1 treatment, suggesting that PLPP1 may be a key metabolic target for improving the anti-tumor function of T cells.
Professor Zhang Yi's team's research work, for the first time, reveals the important relationship between PLPP1 and the anti-tumor function of CD8+ T cells and discovers that the activation of PD-1 signaling inhibits PLPP1 expression in CD8+ T cells. This research clarifies that PLPP1 can serve as a regulator of tumor-infiltrating CD8+ T cell function, which is conducive to improving the efficacy of immunotherapy. Additionally, the discovery that overexpression of PLPP1 can enhance the anti-tumor function of CAR-T cells provides a new research target for genetically engineered T cell modification.
Professor Zhang Yi from the biotherapy center of the First Affiliated Hospital of Zhengzhou University is the corresponding author of this paper. Assistant Researcher Ping Yu, Resident Physician Shan Jiqi, and PhD student Qin Hainam are the first authors. The research project was supported by the National Key R&D Program of China, the National Natural Science Foundation of China and Science and Technology Department of Henan Province.
Article Links: https://www.sciencedirect.com/science/article/pii/S1074761324003765
