By Hendra Lukman 
Researchers at UT Southwestern Medical Center have made a groundbreaking discovery, identifying a specific hormonal pathway that allows cancer cells to evade the body’s immune system. This newly elucidated mechanism, detailed in the prestigious journal Nature Immunology, involves a hormone interacting with a receptor on the surface of crucial immune cells, effectively turning them from cancer fighters into cancer enablers. The implications of this finding are far-reaching, potentially paving the way for novel immunotherapy strategies for cancer treatment, as well as offering new therapeutic avenues for inflammatory disorders and a range of neurologic diseases.
The study, co-led by Professor of Physiology Cheng Cheng "Alec" Zhang, Ph.D., and postdoctoral researcher Xing Yang, Ph.D., both affiliated with UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, pinpoints a critical interaction that subverts the body’s natural defense mechanisms. "Myeloid cells are among the first group of immune cells recruited to tumors," explained Dr. Zhang. "However, very quickly these tumor-fighting cells turn into tumor-supporting cells. Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system." This revelation addresses a significant gap in understanding how cancers develop resistance to immune surveillance, a challenge that has limited the efficacy of existing cancer therapies.
The Immune System’s Double-Edged Sword: Myeloid Cells in Cancer
Myeloid cells represent a diverse group of immune cells that play a pivotal role in both initiating and regulating immune responses. Within the tumor microenvironment, they are typically among the first responders, tasked with identifying and eliminating cancerous cells. However, cancer cells are notoriously adept at manipulating their surroundings, and the tumor microenvironment often becomes a breeding ground for immune suppression. This phenomenon, where immune cells intended to fight cancer are co-opted to support tumor growth, is a central focus of cancer immunology research.
Dr. Zhang highlighted the limitations of current treatments, stating, "Current immunotherapies, such as immune checkpoint inhibitors, are effective for only about 20%-30% of cancer patients." This statistic underscores the urgent need for a deeper understanding of the complex mechanisms by which cancers evade immune detection and destruction. The UT Southwestern study offers a compelling explanation for a portion of these evasive tactics, focusing on the transformation of myeloid cells from allies to adversaries.
Unraveling the LILRB4 Connection
The investigation began several years prior within the Zhang Lab, with researchers diligently studying cancer-fighting immune cells known as myeloid cells. Their work led to the identification of an inhibitory receptor on these cells, dubbed LILRB4 (Leukocyte immunoglobulin-like receptor B4). Crucially, they observed that the stimulation of this LILRB4 receptor had the effect of blocking the myeloid cells’ inherent ability to attack tumors. This initial discovery laid the groundwork for understanding how myeloid cells could be functionally impaired within the tumor microenvironment.
The subsequent phase of the research involved a comprehensive, genome-wide screening effort to identify all proteins that might interact with LILRB4. This meticulous process aimed to uncover the molecular players that could be signaling through this inhibitory receptor. Among the candidates that emerged, a hormone known as SCG2 (Secretogranin II) presented as a particularly promising interaction partner. While SCG2 had been previously suggested to play a role in immune responses, its specific function and the receptor it targeted remained elusive.
SCG2 and LILRB4: A Molecular Alliance Against Immunity
Laboratory experiments provided definitive confirmation of the interaction between SCG2 and LILRB4. The study meticulously demonstrated that SCG2 binds directly to LILRB4 on myeloid cells. This binding event triggers a cascade of intracellular signaling events. The net effect of this signaling cascade is a profound suppression of the myeloid cells’ cancer-fighting capabilities. Furthermore, the study revealed that this interaction also impairs the myeloid cells’ ability to recruit other vital immune cells, specifically cancer-fighting T cells, to the tumor site. This dual action—disabling existing immune defenses and preventing reinforcements—creates a highly favorable environment for tumor progression.
Pre-clinical Evidence: In Vivo Validation of the Mechanism
To validate these findings in a living organism, the researchers employed a sophisticated pre-clinical model. They utilized mice genetically engineered to express the human form of LILRB4, thereby mimicking human immune responses. In these mice, injected cancer cells engineered to produce SCG2 exhibited rapid and aggressive tumor growth. This observation strongly supports the hypothesis that the SCG2-LILRB4 axis directly promotes tumor development.
The therapeutic potential of targeting this pathway was then explored. When these mice were treated with an antibody designed to block LILRB4, a significant deceleration in tumor growth was observed. This outcome indicates that interrupting the SCG2-LILRB4 interaction can effectively restore anti-tumor immunity. Similarly, artificially depleting SCG2 from the animals’ bodies also resulted in a substantial reduction in cancer progression, further solidifying the critical role of this hormone-receptor pair in immune evasion.
These pre-clinical experiments collectively paint a clear picture: the interaction between LILRB4 and SCG2 empowers cancer cells to grow unchecked by the coordinated efforts of myeloid cells, T cells, and potentially other immune cell populations. This discovery offers a tangible target for therapeutic intervention.
Implications for Cancer Immunotherapy: A New Frontier
The identification of the SCG2-LILRB4 pathway opens exciting new avenues for cancer immunotherapy. Dr. Zhang articulated the potential of disrupting this interaction, suggesting that "disrupting this interaction could someday offer a new immunotherapy option to treat cancer." By developing therapies that prevent SCG2 from binding to LILRB4, or by blocking the LILRB4 receptor itself, clinicians might be able to reactivate the immune system’s inherent ability to recognize and destroy cancer cells. This approach could be particularly beneficial for patients who do not respond to current immunotherapies, offering a complementary or alternative treatment strategy.
The research team plans to further investigate the efficacy of blocking this pathway in various cancer models, aiming to translate these promising pre-clinical findings into clinical applications. The development of highly specific antibodies or small molecule inhibitors targeting either SCG2 or LILRB4 could represent a significant advancement in the fight against cancer.
Beyond Cancer: Therapeutic Potential for Inflammatory and Neurologic Diseases
The implications of this discovery extend beyond oncology. The same mechanism that allows cancer cells to suppress immune responses in tumors also holds relevance for conditions characterized by excessive or misdirected immune activity. "Conversely," Dr. Zhang noted, "because this interaction neutralizes myeloid cells’ immune activity, delivering extra SCG2 could be a promising treatment for autoimmune or inflammatory disorders spurred by myeloid cells."
In autoimmune diseases, the immune system mistakenly attacks the body’s own healthy tissues. Similarly, inflammatory disorders involve chronic and harmful inflammation. In many such conditions, myeloid cells are implicated in driving the pathological processes. By using SCG2 therapeutically to dampen the overactive immune response mediated by myeloid cells, it may be possible to alleviate symptoms and slow disease progression in conditions like rheumatoid arthritis, inflammatory bowel disease, or even certain neuroinflammatory conditions.
The research team’s forward-looking plans include exploring these potential therapeutic applications. This dual-use potential—both enhancing anti-cancer immunity and suppressing detrimental immune responses—underscores the fundamental importance of the SCG2-LILRB4 pathway in regulating immune homeostasis.
A Collaborative Effort and Future Directions
This seminal study was a testament to extensive collaboration among researchers at UT Southwestern. In addition to Dr. Zhang and Dr. Yang, key contributors included Xuewu Zhang, Ph.D., Professor of Pharmacology and Biophysics; Cheryl Lewis, Ph.D., Associate Professor in the Simmons Cancer Center and of Pathology; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; Jingjing Xie, Ph.D., Instructor of Physiology; Qi Lou, Ph.D., Assistant Instructor of Physiology; Lei Guo, Ph.D., Computational Biologist; and postdoctoral researchers Meng Fang, Ph.D., Chengcheng Zhang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D.
Dr. Alec Zhang holds the esteemed Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. Dr. Xuewu Zhang and Dr. Xu are both integral members of the Simmons Cancer Center, highlighting the institution’s deep commitment to cancer research.
Funding and Institutional Interests
The research was supported by a robust network of funding bodies, underscoring its significance and potential impact. Grants from the National Cancer Institute (NCI) (R01CA248736, R01CA263079, and Lung Cancer 779 SPORE Development Research Program), the Cancer Prevention and Research Institute of Texas (RP220032, RP15150551, RP190561), The Welch Foundation (AU-0042-20030616, I-1702), Immune-Onc Therapeutics Inc. (Sponsored Research Grant No. 111077), the National Institutes of Health (R35GM130289), and the NCI Cancer Center Support Grant (P30CA142543) were instrumental in enabling this work.
It is also noteworthy that The University of Texas has a financial interest in Immune-Onc Therapeutics Inc., holding equity and licensing agreements. Dr. Alec Zhang has a personal financial interest in Immune-Onc, holding equity and having engaged in sponsored research agreements with the company. These disclosures are standard practice and reflect the ongoing interplay between academic research and its potential for commercial development.
The comprehensive understanding of the SCG2-LILRB4 axis represents a major stride in immunology and oncology. As research progresses, this discovery promises to translate into tangible benefits for patients grappling with cancer and a spectrum of immune-mediated diseases. The meticulous work at UT Southwestern has not only illuminated a critical biological process but has also illuminated a path toward more effective and diversified therapeutic interventions.
