Regulating Cholesterol May Enhance T-Cell Function in Patients With Chronic Lymphocytic Leukemia

Cholesterol regulation may improve T-cell function in patients with chronic lymphocytic leukemia (CLL), offering a novel approach to improving treatment responses and outcomes with immunotherapies. The data were published in Cellular & Molecular Immunology by researchers from Amsterdam University Medical Center in Amsterdam.¹

Visualization of the interaction of cancer cells and T-cells | Image Credit: © Rutchaneewan - stock.adobe.com

CLL is the most common type of leukemia in adults and is expected to be diagnosed in over 23,000 individuals in the United States in 2025 alone. It is characterized by the progressive proliferation of clonal mature B cells, leading to painless swelling of the lymph nodes in the neck, underarm, stomach, or groin that causes fatigue or weakness, fever and infection, or easy bruising or bleeding. CLL outcomes and prognoses have greatly improved with the advent of targeted therapies, namely Bruton’s tyrosine kinase (BTK) inhibitors, which help regulate the B-cell receptor (BCR) signaling pathway to prevent cancer cell growth. However, despite their success, these agents are not curative.^1-3

T-cell-based therapies, such as chimeric antigen receptor (CAR) T-cell therapy, have shown success in the treatment of CLL, but only for a minority of patients. T-cell dysfunction, commonly seen in CLL patients, has been largely implicated as the reason underlying poor responses in CLL. Emerging evidence shows that it is associated with metabolic defects and rapid metabolic shifts, such as altered lipid metabolism, leading to improper T-cell responses and functions. By addressing dysfunction within underlying metabolic mechanisms, there may be an opportunity to enhance T-cell function, thereby improving patients’ responses to therapy.¹

Given these data, researchers from the Netherlands investigated whether lipid metabolism differs in T cells from patients with CLL patients compared with healthy donors (HD). They found that T-cells present in viably frozen samples of patients with CLL demonstrated impaired adaptation to cholesterol deprivation and insufficient activation of essential lipid metabolism regulators.¹

“By a comprehensive, in-depth characterization of key branches of T-cell lipid metabolism, we found that CLL T-cells are highly dependent on exogenous cholesterol for proliferation and fail to increase lipid uptake, synthesis, and utilization within the first 2 days upon TCR [T-cell receptor] engagement, as healthy T cells do,” the researchers wrote.¹

CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). FAO was linked to lower T-cell activation but not proliferation, suggesting that low cholesterol levels are a primary factor limiting T-cell proliferation in CLL. Additionally, CLL T cells had fewer and less organized lipid rafts, which may explain their weakened immune response.¹

The researchers highlight the opportunity for strategies that increase cholesterol availability in CLL T-cells to be applied during the ex vivo manufacturing of CAR T-cell products rather than as systemic treatment to patients. They presented 2 potential strategies: (1) raising intracellular cholesterol levels to enhance T-cell proliferation and CAR T persistence, and (2) boosting FAO to strengthen T-cell activation and support memory cell development.¹

“Strategies improving lipid homeostasis in T cells have the potential to improve depth and duration of CAR-T cell therapy responses by enhancing T-cell activation, proliferation, and ultimately anti-tumor responses,” the researchers concluded. “Not only in CLL but also in other tumors with acquired T-cell dysfunction.”¹

REFERENCES

1. Jacobs C.F., Peters F.S., Camerini E. et al. Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia. Cell Mol Immunol. March 4, 2025. Doi:10.1038/s41423-025-01262-1

2. Key statistics for chronic lymphocytic leukemia. American Cancer Society. January 16, 2025. Accessed March 14, 2025. https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/key-statistics.html

3. Acalabrutinib plus venetoclax superior to chemoimmunotherapy in patients with chronic lymphocytic leukemia. Pharmacy Times. March 11, 2025. Accessed March 14, 2025. https://www.pharmacytimes.com/view/acalabrutinib-plus-venetoclax-superior-to-chemoimmunotherapy-in-patients-with-chronic-lymphocytic-leukemia