By Hendra Lukman 
Researchers at UT Southwestern Medical Center have made a groundbreaking discovery, identifying a critical molecular interaction that allows cancer cells to evade the body’s natural immune defenses. The study, published in the prestigious journal Nature Immunology, details how a specific hormone engages with a receptor on the surface of immune cells, effectively switching off their cancer-fighting capabilities. This revelation holds immense promise for the development of novel immunotherapy strategies to combat cancer, and potentially offers new avenues for treating a range of inflammatory and neurological disorders.
The research, co-led by Dr. Cheng Cheng "Alec" Zhang, Professor of Physiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and Xing Yang, Ph.D., a postdoctoral researcher in the Zhang Lab, sheds light on a complex immune evasion mechanism. "Myeloid cells are among the first group of immune cells recruited to tumors, but very quickly these tumor-fighting cells turn into tumor-supporting cells," explained Dr. Zhang. "Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system." This intricate process highlights a sophisticated strategy employed by tumors to create a microenvironment conducive to their own growth and survival, effectively disarming the body’s frontline defenders.
The Limitations of Current Immunotherapies and the Search for New Targets
The development of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized cancer treatment in recent years. These therapies work by releasing the brakes on the immune system, allowing T cells to recognize and attack cancer cells more effectively. However, their efficacy is limited, with only an estimated 20% to 30% of cancer patients experiencing significant benefit. This statistic underscores the complexity of cancer’s ability to evade immune surveillance and the urgent need for a deeper understanding of the multifaceted mechanisms involved. "Current immunotherapies, such as immune checkpoint inhibitors, are effective for only about 20%-30% of cancer patients," Dr. Zhang noted, emphasizing that "there are multiple ways that cancers evade attack from the immune system." This persistent challenge has driven researchers to explore alternative pathways and molecular targets that contribute to immune suppression within the tumor microenvironment.
A Decade of Discovery: From Inhibitory Receptors to Hormonal Triggers
The journey leading to this pivotal discovery began several years ago within the Zhang Lab, where researchers were meticulously studying myeloid cells – a crucial component of the innate immune system known for its role in both initiating and resolving inflammation, as well as its ability to phagocytose pathogens and cellular debris. During their investigations into how these potent immune cells function within the context of cancer, they identified an inhibitory receptor dubbed LILRB4 (Leukocyte immunoglobulin-like receptor B4). This receptor, when activated, was found to impair the ability of myeloid cells to effectively attack tumor cells. The initial identification of LILRB4 marked a significant step, providing a potential target for modulating immune responses in cancer.
Following the identification of LILRB4, the research team embarked on an ambitious undertaking: a comprehensive, genome-wide screen designed to identify all proteins that might interact with this inhibitory receptor. This exhaustive search was crucial for understanding the upstream signals that could activate LILRB4 and, consequently, dampen anti-tumor immunity. The screen yielded a promising candidate: a hormone known as SCG2 (Secretogranin-II). While SCG2 had been previously implicated in various physiological processes, including neuroendocrine functions and stress responses, its precise role in immune regulation and its cognate receptor remained largely elusive. This lack of clarity presented a compelling research question, and the Zhang Lab was poised to unravel its connection to LILRB4.
Confirming the Molecular Partnership: SCG2 and LILRB4
Laboratory experiments were meticulously designed and executed to validate the suspected interaction between SCG2 and LILRB4. These experiments unequivocally confirmed that SCG2 binds directly to the LILRB4 receptor. This binding event triggered a cascade of intracellular signaling events, a process known as a signaling cascade. The consequence of this cascade was profound: it effectively silenced the cancer-fighting machinery of myeloid cells. Not only did it inhibit their direct cytotoxic activity against tumor cells, but it also impaired their ability to recruit cancer-fighting T cells – the adaptive immune system’s highly specific assassins – to the tumor site. This dual action of SCG2, mediated through LILRB4, creates a formidable shield around the tumor, rendering it invisible and invulnerable to immune attack.
Pre-clinical Evidence: In Vivo Validation of the SCG2-LILRB4 Axis
To further solidify their findings, the researchers moved to pre-clinical models. They utilized mice genetically engineered to express the human form of LILRB4, creating a system that closely mimicked human immune responses. In these mice, injected cancer cells engineered to produce SCG2 exhibited rapid and aggressive tumor growth. This observation strongly suggested that the presence of SCG2, acting through LILRB4, directly promoted tumor progression.
Crucially, the team then tested therapeutic interventions aimed at disrupting this newly identified pathway. Treatment with an antibody designed to block the LILRB4 receptor significantly slowed the growth of these tumors. This demonstrated that inhibiting the interaction between SCG2 and LILRB4 could effectively re-engage the immune system against the cancer. In parallel experiments, artificially reducing the levels of SCG2 in the animals’ bodies also led to a notable deceleration in tumor growth, providing further compelling evidence for the pivotal role of this hormone-receptor axis in promoting cancer progression. These in vivo studies provided a critical bridge between molecular discovery and potential therapeutic application, offering tangible hope for new treatment strategies.
Implications for Cancer Therapy and Beyond
The convergence of these findings paints a clear picture: the interaction between LILRB4 and SCG2 provides cancer cells with a powerful mechanism to escape detection and destruction by myeloid cells, T cells, and potentially other immune cell types. This understanding opens up exciting new therapeutic possibilities. Dr. Zhang posited that disrupting this detrimental interaction could pave the way for a novel class of immunotherapies. By developing agents that specifically block SCG2 binding to LILRB4, or that otherwise inhibit the downstream signaling, clinicians could potentially unleash the full potential of the immune system to fight cancer. This approach could offer a much-needed alternative or complementary strategy for patients who do not respond to existing immunotherapies.
However, the implications of this discovery extend beyond oncology. The research also revealed a fascinating duality in the function of the SCG2-LILRB4 pathway. Because this interaction neutralizes the immune activity of myeloid cells, it suggests a potential therapeutic application in conditions where an overactive immune response, driven by myeloid cells, is detrimental. For instance, delivering extra SCG2 could be a promising treatment strategy for autoimmune diseases and inflammatory disorders, where the immune system mistakenly attacks the body’s own tissues. By dampening the excessive immune activity of myeloid cells, SCG2 could help to restore immune balance and alleviate symptoms. Dr. Zhang and his colleagues are keen to explore both these therapeutic avenues in their ongoing research.
A Collaborative Endeavor and Future Directions
This significant scientific achievement was the result of a dedicated and multidisciplinary team at UT Southwestern. Beyond the leadership of Dr. Alec Zhang and Dr. Xing Yang, the study benefited from the expertise of 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 fellow postdoctoral researchers Meng Fang, Ph.D., Chengcheng Zhang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D.
Dr. Alec Zhang’s contributions are further recognized by his holding the Hortense L. and Morton H. Sanger Professorship in Oncology and his designation as a Michael L. Rosenberg Scholar in Medical Research. Dr. Xuewu Zhang and Dr. Xu are also integral members of the Simmons Cancer Center, underscoring the institution’s commitment to cancer research.
The research was generously supported by grants from several prominent organizations, including 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). This broad funding base highlights the recognized importance and potential impact of this research.
It is also noteworthy that The University of Texas has a financial interest in Immune-Onc, holding equity and licensing agreements. Dr. Alec Zhang holds equity in Immune-Onc and has had sponsored research agreements with the company. These affiliations, while requiring disclosure, are standard in the landscape of academic-industry collaborations aimed at translating scientific discoveries into tangible therapies.
The future research trajectory is clear: further exploration of the SCG2-LILRB4 axis in both cancer and inflammatory contexts. The potential to develop targeted therapies that can either unleash the immune system against cancer or quell an overactive immune response in autoimmune diseases positions this discovery as a significant advancement in modern medicine. The unraveling of this molecular dialogue between a hormone and an immune cell receptor marks a critical step forward, promising to redefine treatment paradigms for some of humanity’s most challenging diseases.
