A hormone-receptor interplay weakens immunity. Focusing on it may struggle most cancers.
Scientists at UT Southwestern Medical Middle have recognized how a hormone binds to a receptor on immune cells, permitting most cancers cells to evade the physique’s defenses. The research, printed in Nature Immunology, factors to potential new instructions in most cancers immunotherapy and may additionally open avenues for treating inflammatory and neurological circumstances.
“Myeloid cells are among the many first group of immune cells recruited to tumors, however in a short time these tumor-fighting cells flip into tumor-supporting cells. Our research means that receptors on these myeloid cells get stimulated by this hormone and find yourself suppressing the immune system,” stated Cheng Cheng “Alec” Zhang, Ph.D., Professor of Physiology and a member of the Harold C. Simmons Complete Most cancers Middle at UT Southwestern. Dr. Zhang co-led the research with first creator Xing Yang, Ph.D., a postdoctoral researcher within the Zhang Lab.
Dr. Zhang famous that present immunotherapies, similar to immune checkpoint inhibitors, solely profit about 20%-30% of sufferers. This restricted success means that most cancers makes use of a number of methods to flee detection and destruction by the immune system.
Discovery of LILRB4 receptor
A number of years in the past, researchers within the Zhang Lab examined how myeloid cells, a kind of immune cell that usually assaults most cancers, may very well be suppressed. They recognized an inhibitory receptor referred to as LILRB4, and when this receptor was activated, the myeloid cells misplaced their means to focus on tumors.
Constructing on that discovery, Dr. Zhang, Dr. Yang, and their workforce performed a genome-wide seek for proteins that work together with LILRB4. One sturdy candidate was a hormone often called SCG2. Whereas earlier research hinted that SCG2 would possibly affect immune exercise, its exact function and receptor weren’t established. Laboratory checks confirmed that SCG2 binds on to LILRB4, triggering a signaling cascade that shut down the tumor-fighting perform of myeloid cells and prevented them from recruiting T cells to assault tumors.
In mice genetically altered to specific the human type of LILRB4, injected most cancers cells that produced SCG2 grew quickly as tumors. Treating these mice with an antibody that blocks LILRB4 considerably slowed most cancers progress, as did artificially ridding the animals’ our bodies of SCG2.
Collectively, these experiments counsel that interactions between LILRB4 and SCG2 enable most cancers to develop unchecked by myeloid cells, T cells, and probably different immune cell sorts. Dr. Zhang recommended that disrupting this interplay may sometime supply a brand new immunotherapy choice to deal with most cancers. Conversely, as a result of this interplay neutralizes myeloid cells’ immune exercise, delivering additional SCG2 may very well be a promising therapy for autoimmune or inflammatory problems spurred by myeloid cells. Dr. Zhang and his colleagues plan to analyze each concepts in future research.
Reference: “Secretogranin 2 binds LILRB4 leading to immunosuppression” by Xing Yang, Ryan Huang, Meng Fang, Yubo He, Jingjing Xie, Xiaoye Liu, Chengcheng Zhang, Qi Lou, Mi Deng, Wei Xiong, Cheryl Lewis, Zade Sadek, Ankit Gupta, Lianqi Chen, Xuewu Zhang, Lei Guo, Lin Xu, Ningyan Zhang, Zhiqiang An and Cheng Cheng Zhang, 24 July 2025, Nature Immunology.
DOI: 10.1038/s41590-025-02233-4
This research was funded by grants from the Nationwide Most cancers Institute (NCI) (R01CA248736, R01CA263079, and Lung Most cancers 779 SPORE Improvement Analysis Program), the Most cancers Prevention and Analysis Institute of Texas (RP220032, RP15150551, RP190561), The Welch Basis (AU-0042-20030616, I-1702), Immune-Onc Therapeutics Inc. (Sponsored Analysis Grant No. 111077), the Nationwide Institutes of Well being (R35GM130289), and NCI Most cancers Middle Help Grant (P30CA142543).
The College of Texas has a monetary curiosity in Immune-Onc within the type of fairness and licensing. Dr. Alec Zhang holds fairness in and had sponsored analysis agreements with Immune-Onc.
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