Blocking energy pathway reduces GVHD while retaining anti-cancer effects of T-cells

November 05, 2020

MUSC Hollings Cancer Center researchers identified that blocking an alternative energy pathway for T-cells after hematopoietic stem cell transplant helps reduce graft-versus-host disease (GVHD) in an animal model of leukemia.

Xue-Zhong Yu, M.D., who also is associate director of Basic Science at Hollings, and collaborators at the Indiana University School of Medicine discovered that donor T-cells must have the key enzyme lysosomal acid lipase in order to induce GVHD.

The Yu laboratory focuses on understanding the biological balance between GVHD and graft-versus-leukemia effect. Hematopoietic stem cell transplantation is used as a treatment option for some leukemia patients. T-cells in stem cell grafts from a donor are given to a leukemia patient in order to kill the cancer and reboot the patient's immune system. GVHD is a big clinical challenge because the donor T-cells, which come from the bone marrow, can attack the patient's organs. Anywhere from 30% to 70% of patients develop acute GVHD after allogeneic bone marrow transplant and 15% die.

"When we deal with hematopoietic cell transplant, it is an important balance - blocking GVHD while still allowing T-cells to do their job and control the cancer," Yu said.

Each cell in our body has its own metabolic process. Cells convert the food that is eaten into energy in order to perform their intended functions. However, cellular metabolism is often altered in various diseases. Yu researches T-cell metabolism in order to understand the balance between graft-versus-host and graft-versus-leukemia responses.

Most cells in our body require oxygen to create energy efficiently. However, this research focused on lipid, or fat, metabolism. T-cells have special metabolic processes: Sometimes they multiply so rapidly that they need an extra source of energy from free fatty acids.

Lysosomal acid lipase is an enzyme that breaks the large lipids and cholesterol into individual free fatty acid building blocks. If that enzyme is missing, there are not enough free fatty acids for energy production. This changes the T-cell metabolism, which in turn changes T-cell function.

Clinically, broad spectrum immunosuppression drugs (steroids and rapamycin) are still used as the first line of care in patients with severe GVHD. However, Yu and collaborators hypothesized that changing T-cell metabolism could reduce GVHD after hematopoietic stem cell transplantation.

"We know that the gut is the primary organ affected by GVHD. Since the gut has less oxygen, the T-cells rely on free fatty acids and must use lysosomal acid lipase. We thought if we could remove or block the activity of that, we could reduce GVHD in the gut."

The Yu Laboratory collaborated with the Indiana University School of Medicine and used a lysosomal acid lipase-deficient mouse model. T-cells lacking lysosomal acid lipase were given to mice with leukemia. As a control, T-cells with lysosomal acid lipase from normal mice were given to another group of leukemia mice. Strikingly, the mice that received the T-cells without lysosomal acid lipase did not get severe GVHD. Additionally, the T-cells from the donor lysosomal acid lipase-deficient bone marrow still killed the leukemia cells.

To increase the clinical translational potential of the work, orlistat, the FDA-approved lysosomal acid lipase inhibitor was also tested in the leukemia model. Mice with leukemia were treated with orlistat every other day after receiving bone marrow from normal mouse donors. Similar to the first experiment with the lysosomal acid lipase-deficient bone marrow, blocking the activity of lysosomal acid lipase with orlistat greatly reduced GVHD while the graft-versus-leukemia effect was preserved.

Additionally, the researchers discovered that inhibiting the lysosomal acid lipase enzyme with orlistat reduced the number of pathogenic T-cells and increased the number of regulatory T-cells. The pathogenic T-cells are the ones that cause GVHD. Regulatory T-cells are one of the "braking mechanisms" of the immune system. They help to reduce the activity of the pathogenic T-cells and prevent GVHD damage.

Therefore, blocking lysosomal acid lipase activity with orlistat preferentially stopped the donor T-cells from damaging the gut but allowed the T-cells to function during circulation and kill the leukemia cells.

The researchers' future plan is to look deeper at the biological mechanisms. For example, it is not clear how the loss or inhibition of lysosomal acid lipase affects the other metabolites in T-cells. To move this finding closer to the clinic, Yu explained that human cells can be used in a special mouse model that recreates the human immune environment.

"Looking at the immune cells in the gut was technically challenging. However, the results were exciting because our hypothesis was validated. These results encourage us to continue studying this in order to provide better treatment options to patients."
-end-
About MUSC

Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and nearly 800 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2019, MUSC set a new high, bringing in more than $284 million. For information on academic programs, visit musc.edu.

As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2019, for the fifth consecutive year, U.S. News & World Report named MUSC Health the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC and its affiliates have collective annual budgets of $3.2 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.

About MUSC Hollings Cancer Center

MUSC Hollings Cancer Center is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.hollingscancercenter.org.

Medical University of South Carolina

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.