12.01.20

Blocking a Fatty-Acid Metabolism Pathways Improves GVHD

Researchers at the Medical University of South Carolina (MUSC) Hollings Cancer Center have demonstrated a new way control graft versus host disease (GVHD) and tumor relapse after hematopoietic cell transplant using experimental animals and cell models.

The authors showed that blocking a key enzyme (lysosomal acid lipase — LAL), involved in fatty-acid release from lipids, prevented GVHD effects while maintaining the beneficial graft versus leukemia (GVL) anti-tumor effect.

The Yu lab’s research focused on the biology of T-cells, micro-RNAs, regulatory T-cells, and metabolic pathways involved in GVHD and leukemia relapse with the goal of preventing GVHD and preserving GVL.

Allogeneic hematopoietic stem cell transplant involves receiving donor bone marrow, umbilical cord stem cells, or peripheral stem cells. The donor is genetically matched and can be related or unrelated to the recipient. This form of therapy is approved for certain cancers such as lymphoma, leukemia and multiple myeloma, and offers a potential cure by transplanting healthy bone marrow cells from a partially matching donor into a patient with cancer.

Unfortunately, current limitations of this therapy include GVHD – an adverse effect where the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign, and the donated immune cells attack the recipient’s organs leading to potentially life-threatening illness. To prevent GVHD, patients are often prescribed immunosuppressant drugs to dampen this immune response. Such drugs may have severe side effects, presenting an unmet medical need to develop better, more specific drugs.

Immune cells have metabolic demands requiring energy sources such as carbohydrates, sugars, and fat to function. Previous studies and the current work demonstrate the importance of energy balance in T-cells, specifically how fatty acids fine-tune and regulate T-cells function. This research shows the importance of LAL, an enzyme which breaks down large fatty acids into building blocks to fuel the high energy demands of T-cells, allowing them to survive, proliferate, and function to mediate anti-tumor response.

By using a LAL specific knockout mouse – which does not have the LAL gene – the authors were able to demonstrate a significantly less severe GVHD response in T-cells lacking LAL.

Further, the authors used a prescription weight-loss drug “Orlistat” (trade name Xenical), which blocks LAL to see if this would also improve GVHD. Their findings demonstrate that it is possible to target LAL both genetically and pharmacologically to control GVHD. The authors further demonstrate that this is because blocking LAL in T-cells impaired their survival, function, and proliferation.

Interestingly, the improvements in GVHD symptoms were more profound in the gut of transplant recipients, suggesting other influences such as the microenvironment of the tissue. Patients with GVHD commonly experience gastrointestinal issues as some of the first symptoms. The authors further speculate that, since the gut has less available oxygen, the T-cells must rely on fatty acids generated by LAL as their primary energy source. Therefore, blocking LAL where T-cells need fatty acids helps to stop them from attacking the gut, and may provide relief to GVHD.

Overall, this work helps guide GVHD research and the development of new, more target-specific drugs for GVHD treatment. Although more research is needed to determine a precise biological mechanism for how LAL works in T-cells, this new avenue provides a promising alternative to broad-spectrum immunosuppressant drugs.

Reference:

Nguyen, H. D., et al. (2020) Lysosomal Acid Lipase Is Required for Donor T Cells to Induce Graft-versus-Host Disease. Cell Reports. doi.org/10.1016/j.celrep.2020.108316.

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