UTSW scientists identify cancer-suppressing genetic mutation
Findings could eventually lead to improved immunotherapies for melanoma, other cancers
DALLAS – Dec. 23, 2024 – UT Southwestern Medical Center researchers identified a genetic mutation that slows the growth of melanoma and potentially other cancers by harnessing the power of the immune system. Their findings, published in the Journal of Experimental Medicine, could lead to new treatments that improve outcomes from existing cancer immunotherapies.
“Our findings suggest a completely new type of therapeutic target that could someday be used to suppress a wide range of cancers,” said Hexin Shi, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.
Dr. Shi co-led the study with Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine. Dr. Beutler was awarded the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of receptors that allow mammals to quickly sense infection and trigger an inflammatory response. He is also a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center at UTSW.
Researchers have identified many genes, known as oncogenes, that initiate and drive cancer when mutated. Although scientists have long speculated that mutations protecting against cancer also exist in the human genome, Dr. Shi explained, finding them by studying human subjects has been difficult because people carrying these genetic variants don’t show any obvious differences compared to others.
To search for genes that confer tumor resistance, Drs. Shi and Beutler and UTSW colleagues created mouse models with various genetic mutations and then searched for mice that didn’t develop tumors or had limited cancer growth. Next, they used a method recently developed in the Beutler Lab called automated meiotic mapping (AMM), which traces unusual features of interest in mutant mice to the causative mutations.
The researchers quickly homed in on a gene called H2-Aa. Mice carrying two mutated copies of this gene, causing them to completely lack the H2-Aa protein, often showed no tumor growth after exposure to melanoma cells. Those carrying one mutant copy had significantly reduced growth compared with mice carrying strictly the “wild type” form of the gene. H2-Aa is responsible for producing part of an immune protein called MHC class II, which helps the immune system distinguish self-proteins from non-self-proteins, readying it to attack potential invaders.
Using genetic engineering, the researchers narrowed H2-Aa’s cancer-supporting function to its presence on the surface of a subclass of immune cells called dendritic cells. Eliminating H2-Aa in only these cells was enough to mimic having the absence of H2-Aa throughout the body. When the researchers compared tumors that developed in wild-type mice and those in mice lacking H2-Aa, the tumors in mutant mice were infiltrated with more dendritic cells as well as more tumor-fighting CD8 T cells, and far fewer regulatory T cells that suppress anticancer immune activity.
Seeking a pharmaceutical that could produce the same effects as mutant H2-Aa, the researchers developed a monoclonal antibody – a protein that blocks the effects of other proteins – against H2-Aa. Although the antibody had considerable anticancer effect when delivered to mice with melanoma tumors, its effect was greatly enhanced when the researchers also treated the same mice with a checkpoint inhibitor drug, a type of immunotherapy. On the other hand, without monoclonal antibodies against H2-Aa, checkpoint inhibitors had no effect on cancer growth.
Dr. Beutler suggested monoclonal antibodies targeting the human form of this and other closely related proteins could have a similar effect, serving as a viable cancer treatment on its own or as a boost to immunotherapy treatments. This idea might eventually be tested in clinical trials, he said.
“One-half to two-thirds of melanoma patients don’t respond to checkpoint inhibitors,” Dr. Beutler said. “These findings might be very useful if we could help everyone respond to them.”
Other UTSW researchers who contributed to this study are Chao Xing, Ph.D., Professor in the Eugene McDermott Center for Human Growth and Development, the Lyda Hill Department of Bioinformatics, and the Peter O’Donnell Jr. School of Public Health; Xiaohong Li, M.D., Ph.D., Jiexia Quan, Ph.D., Sara Ludwig, Ph.D., and Eva Marie Moresco, Ph.D., Assistant Professors in the Center for the Genetics of Host Defense and of Immunology; James Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Biophysics; Dawson Medler, B.S., and Rachel Browning, B.S., Research Assistants; Jianhui Wang, M.S., Senior Research Scientist; Aijie Liu, B.S, Senior Research Associate; Sara Schneider, M.S., Research Associate; and Ashwani Kumar, M.S., Computational Biologist.
Dr. Beutler holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. and is a Regental Professor.
This study was funded by National Institutes of Health grants (AI125581 and CA258602) and Pfizer Inc.
Author disclosures can be found in the manuscript.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 24 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.