Hollings Cancer Center researchers study T-cell exhaustion in tumor microenvironment

Hollings Cancer Center researcher Jessica Thaxton, Ph.D., is the recipient of two grants totaling $3.4 million from the National Cancer Institute (NCI) for her work in cancer immunotherapy and cell stress, one of which is part of the Cancer Moonshot Initiative on immunometabolism.

Immunotherapy is a form of cancer treatment that uses patients’ own immune cells to fight their cancer. Understanding the environment inside a solid tumor, the microenvironment, is very important. Immune cells may enter a tumor in an attempt to kill the tumor, but the tumor interior is harsh. Thus, the tumor-infiltrating immune cells face a profound stress that compromises their function. It is very likely that immunotherapy is most successful in patients who have less suppressive, less harsh microenvironments, she explained.

“I like to think that we are looking at immunotherapy with a different lens” said Thaxton, an assistant professor in the College of Medicine at the Medical University of South Carolina.

Thaxton’s lab studies the stress that the immune cells face in the tumor microenvironment in order to discover ways to overcome this challenge and invigorate immunity against tumors. The two NCI grants are both related to investigating CD8 T-cells in the solid tumor microenvironment; however, they have different approaches.

One project, Exploitation of ER Stress Induced Immune Dysfunction to Improve Immunotherapy, investigates how the T-cell responses to stress in the tumor microenvironment undermines their ability to generate energy to fight tumor growth. The second project looks at how the stress response drives exhaustion in T-cells and the effect of the chronic exhaustion on response to checkpoint blockade therapy in sarcoma patients. This research will provide valuable information on how tumor stress changes both T-cell metabolism and function.

Cells have an intrinsic stress response, regulated by a molecule called PERK, that appears to be driving what is wrong with T-cells in the tumor microenvironment. It appears that PERK can determine how a T-cell generates energy in the stress of solid tumors. Moreover, the chronic arm of the stress response is at play in exhausted T-cells, Thaxton said. Exhausted T-cells barely function, but really, those cells should be responding and killing the tumor cells. Therefore, targeting the stress response in cancer patients holds the potential for increasing the efficacy of immunotherapy. Thaxton’s team has shown that targeting the stress response can eliminate solid tumors.

For her current studies, her lab has partnered with other Hollings Cancer Center researchers in order to obtain human tumor samples. One of those collaborations is with Lee Leddy, M.D., who performs surgeries to remove sarcomas. Sarcomas are one of the most immunogenic solid tumors, which means that the tumor provokes an immune response. The Thaxton lab always has found a large number of immune cells in the more than 50 tumor samples that they have received. The immune cells are used to study the intricate stress response pathways in each T-cell. They are also starting to study oral cavity tumors in collaboration with head and neck surgeon David Neskey, M.D.

Thaxton, who uses animal models and human studies, said she prefers the combination of basic and translational sciences to ensure that the research stays clinically relevant and can be used to create new therapies for patients. As a clinical research institution, MUSC is well-suited for preclinical research, explained Thaxton, who started her lab four year ago and credits her early success to the Paul Calabresi Clinical Oncology NCI K Award. It funded her research from 2016 to 2019.

“Many research teams are studying similar components, or themes, in cancer research. The Calabresi award gave me more time to figure out what I can do differently in cancer immunotherapy research. I looked at what other researchers were doing and determined where there was a gap in research and devised a way to fill that need.”

Thaxton’s lab operates in a team environment, which makes it easier to facilitate connections between the various animal and human experiments. Lab manager Katie Hurst has been influential in driving the research forward, particularly since her pursuit of an MUSC Master of Public Health degree has enhanced ongoing disparities cancer research at Hollings. By recruiting researchers with a variety of skills and strengths, Thaxton said it has enabled her to develop a strong foundation for groundbreaking cancer research. “Now the lab has recruited members with molecular and biochemical expertise so that we can continue to address hard to study questions in tumor immunotherapy,” she added.

Based on the early success with T-cells, the lab also will explore tumor-driven stress in other immune cells, such as macrophages and natural killer cells. This broad scope will help to piece together the growing puzzle in the understanding of patients’ immune systems and cancers.

“Overall, I am most proud of the fact that we’re taking a different approach to cancer immunotherapy by targeting the T-cell stress response,” Thaxton said. “This work will inform drug development and holds immense promise to generate better therapies for cancer patients.”

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About the Medical University of South Carolina

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 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 http://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 number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.org.

MUSC and its affiliates have collective annual budgets of $3 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers

About Hollings Cancer Center

The Hollings Cancer Center at the Medical University of South Carolina 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