By Hendra Lukman 
Researchers at UT Southwestern Medical Center have made a groundbreaking discovery, identifying a critical molecular mechanism by which cancer cells evade the body’s immune surveillance. Their findings, published in the prestigious journal Nature Immunology, detail how a specific hormone, SCG2, interacts with a receptor on the surface of key immune cells, effectively disarming them and creating a protective shield around tumors. This revelation holds significant promise for the development of novel immunotherapies for cancer, and potentially for new therapeutic strategies targeting inflammatory and neurological disorders.
The Unforeseen Alliance: SCG2 and LILRB4
The intricate dance between cancer and the immune system is a complex battleground, and UT Southwestern scientists have illuminated a previously unknown alliance that tips the scales in favor of the malignancy. At the heart of this discovery lies the interaction between the hormone SCG2 and the inhibitory receptor LILRB4, which is found on the surface of myeloid cells. Myeloid cells are a crucial component of the innate immune system, acting as the first responders to any perceived threat, including the emergence of cancerous growths. However, the research indicates that under the influence of SCG2, these vigilant defenders can be coerced into becoming unwitting accomplices of the tumor.
"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 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, who co-led the study with first author Xing Yang, Ph.D., a postdoctoral researcher in his lab, elaborated on the mechanism: "Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system."
This finding is particularly significant given the limitations of current cancer treatments. Dr. Zhang noted that existing immunotherapies, such as immune checkpoint inhibitors, achieve significant success in only a fraction of patients, estimated to be around 20%-30%. This statistic underscores the multifaceted nature of cancer’s ability to elude immune detection and destruction, prompting a continuous search for new therapeutic targets.
A Journey of Discovery: From Inhibitory Receptor to Hormonal Partner
The genesis of this research can be traced back several years to investigations within the Zhang Lab focused on myeloid cells, a diverse group of immune cells that play a pivotal role in both immunity and disease. During this earlier work, researchers identified an inhibitory receptor on these cells known as LILRB4. They observed that when this receptor was stimulated, it effectively blunted the myeloid cells’ capacity to combat tumors. This initial observation hinted at a regulatory pathway that could be exploited by cancer.
The subsequent phase of the research involved a comprehensive, genome-wide screen conducted by Dr. Zhang, Dr. Yang, and their colleagues. Their objective was to identify all proteins that might interact with LILRB4. Among the many potential candidates, one stood out as particularly promising: the hormone SCG2. While SCG2 had been previously hypothesized to be involved in immune responses, its precise function and its cellular receptor remained elusive.
Through meticulous laboratory experiments, the team confirmed their hypothesis. They demonstrated conclusively that SCG2 binds directly to LILRB4. This binding event triggers a cascade of intracellular signals within the myeloid cells. This signaling pathway, once activated, effectively silences the cancer-fighting capabilities of these immune cells. Furthermore, the study revealed that this SCG2-LILRB4 interaction also impairs the myeloid cells’ ability to recruit other crucial cancer-fighting immune cells, specifically T cells, to the tumor site. T cells are the body’s specialized assassins, programmed to identify and eliminate cancerous cells, and their absence or suppression is a significant boon for tumor growth.
Pre-clinical Validation: Evidence from the Animal Model
To further validate their findings, the researchers conducted experiments in mice. They utilized mice that were genetically engineered to express the human form of LILRB4, mimicking the human immune system’s response. In these mice, when cancer cells engineered to produce SCG2 were injected, they exhibited rapid and aggressive tumor growth. This observation provided compelling evidence that the SCG2-LILRB4 axis directly promotes tumor progression.
Crucially, the researchers then tested the therapeutic potential of targeting this newly identified pathway. They treated these tumor-bearing mice with an antibody designed to block LILRB4. The results were significant: treatment with this antibody markedly slowed the growth of the tumors. In a complementary experiment, they also explored the effect of artificially reducing the levels of SCG2 in the animals’ bodies. This intervention also led to a significant reduction in cancer growth, further solidifying the role of SCG2 as a tumor facilitator.
These pre-clinical studies collectively suggest a powerful mechanism by which cancer exploits the immune system: the interaction between SCG2 and LILRB4 allows tumors to grow unimpeded by the defensive actions of myeloid cells and T cells, and potentially by other immune cell types as well.
Implications for Future Therapies: Targeting Cancer and Beyond
The implications of this discovery are far-reaching and offer a dual-pronged approach to therapeutic intervention.
For Cancer Treatment: Dr. Zhang proposed that disrupting the SCG2-LILRB4 interaction could pave the way for a novel class of immunotherapies. By blocking this specific signaling pathway, it might be possible to reawaken the dormant anti-cancer defenses of myeloid cells and enable them to effectively target and destroy tumors. This approach could potentially benefit patients who do not respond to existing immunotherapies, expanding the reach of cancer treatment. The development of SCG2-blocking agents or LILRB4-antagonizing antibodies could represent a significant advancement in the fight against cancer.
For Inflammatory and Neurologic Disorders: Intriguingly, the research also points towards the potential of this discovery for treating conditions characterized by an overactive immune response, such as autoimmune diseases and inflammatory disorders. Since the SCG2-LILRB4 interaction effectively neutralizes the immune activity of myeloid cells, delivering extra SCG2 could act as a potent immunosuppressant. This could be beneficial in conditions where myeloid cells contribute to pathological inflammation and tissue damage. Diseases like rheumatoid arthritis, inflammatory bowel disease, and even certain neurodegenerative conditions that involve chronic inflammation could potentially be targeted by this strategy.
Dr. Zhang and his colleagues are actively pursuing both of these avenues in their ongoing research, aiming to translate these fundamental discoveries into tangible clinical benefits.
A Collaborative Effort and Funding Landscape
This pivotal research was a testament to the collaborative spirit at UT Southwestern Medical Center, involving a multidisciplinary team of scientists. In addition to Drs. Zhang and Yang, other 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.
The research was generously supported by a robust funding ecosystem, underscoring the national and institutional commitment to advancing cancer and immunology research. Key grants were provided by 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).
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 also holds equity in and has had sponsored research agreements with Immune-Onc, reflecting the translation of academic research into potential commercial applications.
The Broader Context: The Evolving Landscape of Cancer Immunotherapy
The discovery of the SCG2-LILRB4 axis arrives at a time of unprecedented innovation in cancer immunotherapy. For decades, cancer treatment primarily relied on surgery, radiation, and chemotherapy, all of which aim to directly attack cancer cells or inhibit their growth. While effective, these modalities often come with significant side effects and limitations.
The advent of immunotherapy has revolutionized cancer care by harnessing the power of the patient’s own immune system to fight the disease. Immune checkpoint inhibitors, which block proteins that prevent T cells from attacking cancer, have become a cornerstone of treatment for many cancers, including melanoma, lung cancer, and kidney cancer. However, as noted, their efficacy is not universal.
This new finding from UT Southwestern adds a critical piece to the puzzle of immune evasion. It highlights that cancer cells can manipulate not only the direct attackers like T cells but also the initial responders like myeloid cells. Understanding these complex interactions is crucial for developing more sophisticated and broadly effective immunotherapies.
The identification of SCG2 and LILRB4 as key players in this immune suppression opens up new avenues for drug development. The focus will likely shift towards therapies that can:
- Block the SCG2-LILRB4 interaction: This would involve developing antibodies or small molecules that prevent SCG2 from binding to LILRB4, thereby restoring the anti-tumor functions of myeloid cells and enabling T cell recruitment.
- Target SCG2 production: Inhibiting the synthesis or release of SCG2 by cancer cells or other cells in the tumor microenvironment could also disrupt this immunosuppressive pathway.
- Modulate LILRB4 signaling: While blocking is one approach, there might also be ways to fine-tune LILRB4 signaling to achieve a desired immune response.
Beyond cancer, the potential application in inflammatory and autoimmune diseases is equally exciting. These conditions are often driven by an overzealous immune system, and the ability to selectively dampen immune cell activity through the SCG2 pathway could offer a targeted and potentially safer therapeutic approach compared to broad immunosuppressants.
The research by Dr. Zhang, Dr. Yang, and their colleagues represents a significant leap forward in our understanding of the intricate interplay between cancer and the immune system. It underscores the importance of continued investment in fundamental research to uncover the hidden mechanisms of disease and to develop the next generation of life-saving therapies. The journey from laboratory discovery to clinical application is often long, but this groundbreaking work provides a clear and promising direction for future medical advancements.