Mechanism of Immune Escape Uncovered by UT Southwestern Researchers
Researchers at UT Southwestern Medical Center have elucidated the interaction between a hormone and a receptor on the surface of immune cells, highlighting how this relationship allows cancer cells to evade the body’s natural defenses. The findings, published in Nature Immunology, hold promise for new immunotherapy approaches to treat cancer, as well as potential interventions for inflammatory disorders and neurological diseases.
Insights from the Study
“Myeloid cells are among the first immune cells recruited to tumors, yet these tumor-fighting cells can quickly become tumor-supporting cells. Our study indicates that receptors on these myeloid cells are stimulated by this hormone, ultimately leading to immune suppression,” stated Cheng Cheng “Alec” Zhang, Ph.D., Professor of Physiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Zhang co-led the investigation alongside first author Xing Yang, Ph.D., a postdoctoral researcher in the Zhang Lab.
Current Limitations in Immunotherapy
Current immunotherapies, such as immune checkpoint inhibitors, demonstrate efficacy in only approximately 20%-30% of cancer patients, indicating the presence of multiple mechanisms by which cancers can evade immune system attacks, according to Dr. Zhang.
Discovery of LILRB4 and SCG2
In previous studies, researchers in the Zhang Lab focused on myeloid cells and identified an inhibitory receptor known as LILRB4. Activation of this receptor impeded the ability of myeloid cells to combat tumors.
The team conducted a genome-wide screen of proteins that might interact with LILRB4, leading to the identification of a hormone called SCG2. While its involvement in the immune response was suggested, its specific function and receptor remained unclear. Laboratory experiments confirmed that SCG2 binds to LILRB4, initiating a signaling cascade that diminishes the cancer-fighting capabilities of myeloid cells and reduces their ability to attract T cells to tumors.
Experimental Evidence and Implications
Experiments conducted on genetically altered mice expressing the human form of LILRB4 revealed that cancer cells producing SCG2 proliferated rapidly. Treatment with an antibody that blocks LILRB4 substantially slowed tumor growth, as did the elimination of SCG2 from the animals’ systems.
These findings suggest that the interaction between LILRB4 and SCG2 permits unchecked cancer growth by inhibiting the activity of myeloid cells, T cells, and potentially other immune cell types. Dr. Zhang proposed that disrupting this interaction could provide a novel immunotherapy option for cancer treatment. Conversely, as this interaction suppresses myeloid cell immune activity, increasing SCG2 levels could offer a promising treatment avenue for autoimmune or inflammatory disorders associated with myeloid cells. Future studies are planned to further investigate both hypotheses.
Contributors and Funding
Other contributors to this study from UT Southwestern include Xuewu Zhang, Ph.D., Cheryl Lewis, Ph.D., Lin Xu, Ph.D., Jingjing Xie, Ph.D., Qi Lou, Ph.D., Lei Guo, Ph.D., and postdoctoral researchers Chengcheng Zhang, Ankit Gupta, and Lianqi Chen, among others.
Dr. Alec Zhang holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. Drs. Xuewu Zhang and Xu are also members of the Simmons Cancer Center.
This study received funding from various organizations, including the National Cancer Institute (NCI), the Cancer Prevention and Research Institute of Texas, The Welch Foundation, and Immune-Onc Therapeutics Inc.
Furthermore, the University of Texas maintains a financial interest in Immune-Onc through equity and licensing arrangements. Dr. Alec Zhang holds equity in and has engaged in sponsored research agreements with Immune-Onc.
Key Health Takeaway
The interaction between the hormone SCG2 and the receptor LILRB4 on immune cells presents a significant avenue for future research in cancer immunotherapy, with implications for both enhancing cancer treatments and developing new interventions for inflammatory conditions.
