Modulating Cholesterol Metabolism Could Open Therapeutic Pathways in CLL

Faulty lipid regulation appears to play a key role in T cell dysfunction in patients with chronic lymphocytic leukemia (CLL), a new study found. The findings, which were reported in the journal Cellular & Molecular Immunology, suggest that modulating cholesterol metabolism in patients with CLL could improve T-cell function and thereby open up new therapeutic avenues to treat the disease.1

Corresponding author Helga Simon-Molas, PhD, of the University of Amsterdam, and colleagues, explained that Bruton tyrosine kinase inhibitors and BCL-2 inhibitors have led to dramatic reshaping of the treatment landscape in CLL in recent years. However, neither class of drugs is curative, and many patients develop resistance to the therapies.2 Patients with resistance to both classes of therapies face a particularly dismal prognosis, studies indicate.

“Hence, an unmet medical need exists for additional therapeutic strategies with curative potential,” they wrote.

Modulating cholesterol metabolism in patients with CLL could improve T-cell function and possibly open up new therapeutic avenues to treat the disease. | Image credit: keetazalay - stock.adobe.com

One possible therapeutic solution is autologous T-cell therapies, including chimeric antigen receptor (CAR) T-cell therapies. Yet, Simon-Molas and colleagues explained despite success in other hematological malignancies, T-cell therapies have proven ineffective in the majority of patients with CLL. The problem, they said, is believed to be T-cell dysfunction associated with CLL. What is unclear, though, is exactly why patients with CLL have dysfunctional T cells.

Simon-Molas and colleagues decided to compare the T-cell lipid metabolism of patients with CLL to that of age-matched healthy donors. They identified a number of differences, including a reduced uptake of exogenous cholesterol, an impaired ability to initiate de novo fatty acid synthesis, decreased fatty acid oxidation (FAO), lower relative levels of phospholipids and cholesterol, and increased triacylglycerols storage.

To pinpoint the role of FAO impairment, the investigators also analyzed samples from patients with inherent FAO disorders. They found that the decrease in oxidation leads to lower T-cell activation, though it did not affect T-cell proliferation. Thus, they said, it is likely that lower cholesterol levels are the primary cause of limited T-cell proliferation in CLL.

“Our findings demonstrate that cholesterol is crucial for T-cell proliferation, serving as a key component of new membranes and lipid rafts, while mitochondrial FAO supports T-cell activation and it is not essential for proliferation,” they wrote.

The investigators said the altered lipid metabolism identified in their study suggests a number of potential therapeutic possibilities for CLL. They posited that increasing lipid uptake and synthesis in patients with CLL might have the effect of rebalancing lipid homeostasis and reversing T-cell dysfunction.

Further, they argued that increasing cholesterol availability in CLL T cells might be the most promising way to solve the problem. They said the strategy would not necessarily require systemic treatment, but instead could be applied to the manufacturing process for CAR-T cell therapies. One strategy would be to increase the availability of intracellular cholesterol, they said, which could boost T-cell proliferation and improve the efficacy of CAR-T cells. Another strategy would be to increase FAO in order to increase T-cell activation and the acquisition of a memory phenotype. They said similar research on overexpressing lipid-related genes affirms the potential benefits of such an approach, though they said there might be limits to how much transcription factor activity can be controlled.

Simon-Molas and colleagues said their findings suggest improvement of lipid homeostasis in T cells may be an important strategy to improve the depth and duration of CAR T-cell therapy responses in patients with CLL, but they added that the strategy might also prove effective in other types of cancers in which T-cell dysfunction has been reported.

References

1. Jacobs CF, Peters FS, 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. Published online March 4, 2025. doi:10.1038/s41423-025-01262-1
2. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083