Johns Hopkins All Children's Researchers Make Discovery That May Advance Cancer Immunotherapy
Beginning in the 1960s and finding a true niche in cancer therapy by the 1990s, “immunotherapy,” also called “adoptive therapy,” has successfully advanced the treatment for several kinds of cancer.
The concept behind immunotherapy entails finding ways to enlist the patient’s own immune system in the fight against cancer. In recent years, several kinds of immunotherapies have been successfully incorporated into clinical practice and are being used to treat a variety of cancers.
For example, “checkpoint inhibitors” are drugs used to help the immune system recognize and attack cancer cells. Chimeric antigen receptor (CAR) T-cell therapy extracts important immune cells, called “T-cells,” from a patient's blood and engineers them to target specialized protein receptors on tumor cells. Then the “revved-up” T-cells are injected back into the patient so that the immune cells attach to tumor cells to kill the cancer.
“Cytokine treatment” enlists small proteins to carry messages between cells and aims at stimulating the immune cells to attack cancer. Also, drugs called “immunomodulators” are used to boost parts of the immune system, cancer vaccines have also been developed to increase the immune response, and drugs called “monoclonal antibodies” (mAbs or MoAbs) — man-made versions of immune system proteins — can be designed to attack a very specific part of a cancer cell.
While the immunotherapies noted above have found their place in clinical practice, scientists in the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research in St. Petersburg, Florida, are using basic research in an effort to find new ways to boost the immune system to fight cancer.
New Research in the Institute for Fundamental Biomedical Research
Jianhua Xiong, Ph.D., an assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at the Johns Hopkins School of Medicine and a member of the Institute for Fundamental Biomedical Research at Johns Hopkins All Children’s, have discovered a potential strategy that may open a new immunotherapy window.
Xiong and his colleagues, including those at the National Institutes of Health (NIH) where he once worked, recently published a paper in the journal Molecular Biology of the Cell, the respected research publication of the American Society for Cell Biology. This paper titled “The short-chain fatty acid acetate coordinates with CD30 to modulate T-cell survival” was noted by the reviewers and editors to be of particular interest and significance in Quarterly Highlights.
This study describes their research into how to boost the immune system’s T-cells by treating them with acetate, as acetate metabolism is an important metabolic pathway in many pathological conditions including cancers. The focus of their research was to discover how acetate coordinates with CD30, a receptor, and a member of the tumor necrosis factor (TNF) superfamily, how CD30 expression is tightly controlled in T-cells, and how acetate/CD30 coordination may affect T-cells.
The Role of Acetate and CD30 in T-cell Survival
According to Xiong, CD30 is highly expressed in some malignant cells, but also exists in lesser amounts in a small subset of activated normal lymphocytes, including T-cells — cells important to immune system function.
The researchers knew that cellular metabolism “instructs and modulates” T-cell differentiation and function at multiple levels, and that the lives and deaths of T-cells are “highly dynamic” and tightly regulated. They also knew that acetate affects gene expression, protein stability and cell “fate and function.”
“We hypothesized that acetate might modulate T-cell apoptosis,” Xiong explains.
In the laboratory, the researchers began their research by extracting and treating mouse and human T-cells with acetate. They found that the expression of CD30 protein was markedly increased by treating both mouse and human T-cells, which suggests that acetate is a “metabolic mediator” of CD30, positively regulating CD30’s expression through gene association.
Additionally, they found that acetate not only inhibited the apoptosis of healthy cells, often caused by some kinds of chemotherapy, such as with use of the potent chemotherapy drug doxorubicin, but, playing a dual role, acetate also boosted the effectiveness of T-cells in potentially fighting cancer cells.
“We found that acetate treatment effectively increased the expression of CD30 by enhancing its gene transcription,” Xiong explains. “Once more, our data suggested that increasing acetate levels not only protected T-cells from apoptosis, but that CD30 had an opposing effect on T-cell apoptosis, establishing a regulatory loop formed by acetate and CD30.”
“So, therapeutic manipulation of acetate metabolism may facilitate optimal T-cell responses in pathological conditions, such as cancers,” Xiong explains.
Xiong also noted that, following the publication of their research results, researchers from another institution found that acetate supplementation bolstered T-cell functions and proliferation and promoted both an anti-tumor response and enhanced the efficacy of chemotherapy in preclinical breast cancer models.
The Many Research Interests of Jianhua Xiong, Ph.D.
Xiong, who came to Johns Hopkins All Children’s from the NIH in 2021, has seen his research interests coalesce in the lab he established upon his arrival and where the current research regarding acetate and CD30 coordination adds a new dimension of immunotherapy is being developed. The research reported above reflects just one of his current and overlapping research interests — interests that include the metabolic and cytokine regulation of the fate and function of cells; protein-protein interactions in cell signaling and metabolism; cytokine-mediated regulation of organ homeostasis and metabolism; vascular and immune lineages for cell therapy and drug discovery; and the molecular and cellular interactions in vascular-immune “crosstalk” in health and disease.
Cell Biology as a Calling
For Xiong, research, such as described in the new publication, has been a calling since his youth.
“I found cell biology amazing, and I was fascinated by the work that living cells do,” says Xiong, who received his Ph.D. in biotechnology from the prestigious Peking University.
After receiving his Ph.D., Xiong performed postdoctoral studies at the University of California, San Diego (UCSD) in the Division of Biological Sciences. There, he investigated the mechanism of genetic stability in stem cells, among other areas of related research.
Upon leaving UCSD, Xiong worked at the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), located just outside of Washington, D.C., where, in the Center for Molecular Medicine, from 2014 to 2017, he investigated mechanisms related to “cell fate” and aspects of the vascular and immune systems and their regulation. He then moved to the NHLBI Immunology Center and, from 2017 to 2021, he investigated the mechanisms behind “alternative fates” in the living cells of the immune system and the fundamental processes relevant to a broad range of diseases, including many inherited immunodeficiencies, cardiovascular disease, cancers, and autoimmune and allergic diseases.
Since his arrival at Johns Hopkins All Children’s in 2021, Xiong has been busy building his laboratory staff and working at his passion for learning more about the function of cells by employing cell biology to identify molecular and cellular targets that can be harnessed and used to develop new ways to enhance the immune system or aid in drug discovery. Much of his work is in basic “bench science” that can be translated into treatments for use in clinical practice.
“I am very excited about being here,” Xiong says.