By Hendra Lukman 
Researchers at UT Southwestern Medical Center have made a groundbreaking discovery, identifying a critical mechanism by which cancer cells evade the body’s natural immune defenses. Their findings, published in the prestigious journal Nature Immunology, reveal that a specific hormone, SCG2, interacts with a receptor on the surface of key immune cells, effectively disarming them and allowing tumors to flourish. This revelation holds significant promise for developing novel immunotherapy strategies for cancer treatment, and potentially for addressing inflammatory disorders and neurologic diseases.
The Hijacking of Myeloid Cells: A Cancerous Alliance
The study, co-led by Professor Cheng Cheng "Alec" Zhang, Ph.D., a distinguished member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and postdoctoral researcher Xing Yang, Ph.D., sheds light on a complex cellular interplay. Myeloid cells, a crucial component of the innate immune system, are typically among the first responders to the presence of tumors, tasked with identifying and eliminating cancerous threats. However, the research suggests that these valiant defenders are often subverted.
"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 parasitic relationship, where a natural defense mechanism is turned against the host, represents a significant hurdle in the fight against cancer.
The effectiveness of current cancer immunotherapies, such as immune checkpoint inhibitors, is limited, typically benefiting only 20% to 30% of patients. This statistic underscores the multifaceted strategies cancer employs to evade immune detection and destruction. Dr. Zhang’s team’s work provides a crucial piece of this complex puzzle, illuminating one of the insidious ways tumors achieve this evasion.
A Journey of Discovery: From Inhibitory Receptor to Hormonal Partner
The genesis of this discovery can be traced back several years to earlier work within the Zhang Lab. Researchers had identified an inhibitory receptor on myeloid cells, known as LILRB4. Their initial investigations revealed that when this receptor was stimulated, it effectively crippled the myeloid cells’ ability to mount an attack against tumors. This finding raised a pivotal question: what was stimulating this receptor and disabling these immune sentinels?
To answer this, Dr. Zhang, Dr. Yang, and their colleagues embarked on an extensive genome-wide screen, a systematic search for all proteins that might interact with LILRB4. This meticulous process yielded a promising candidate: a hormone named SCG2 (secretogranin-II). While SCG2 had been previously implicated in immune responses, its precise function and the receptor it targeted remained elusive.
Subsequent laboratory experiments provided the definitive link. The UT Southwestern team confirmed that SCG2 directly binds to the LILRB4 receptor. This binding event triggers a cascade of intracellular signals, a complex molecular signaling pathway that ultimately results in the silencing of the myeloid cells’ tumor-fighting capabilities. Furthermore, the study demonstrated that this SCG2-LILRB4 interaction also inhibits the myeloid cells’ crucial role in recruiting cancer-fighting T cells to the tumor site, effectively creating a double barrier to immune surveillance.
In Vivo Validation: A Preclinical Glimpse of Therapeutic Potential
To validate these findings in a living system, the researchers conducted experiments using mice genetically engineered to express the human form of the LILRB4 receptor. In these models, when cancer cells engineered to produce SCG2 were injected, they rapidly proliferated and formed tumors. This observation strongly suggested a direct correlation between SCG2 production, LILRB4 activation, and tumor growth.
Crucially, the therapeutic implications of this discovery became apparent when the mice were treated. Administration of an antibody designed to block the LILRB4 receptor significantly slowed the growth of these SCG2-producing tumors. Similarly, artificially depleting SCG2 from the animals’ systems also led to a marked reduction in tumor progression. These preclinical results provided compelling evidence that disrupting the SCG2-LILRB4 axis could be a viable strategy for combating cancer.
A Dual-Edged Sword: Implications for Cancer and Autoimmunity
The collective evidence from these experiments paints a clear picture: the interaction between LILRB4 and SCG2 creates an environment where cancer can thrive, shielded from the scrutiny of myeloid cells, T cells, and potentially other immune components. Dr. Zhang articulated the exciting potential of this discovery for future cancer therapies: "Disrupting this interaction could someday offer a new immunotherapy option to treat cancer."
However, the implications of this research extend beyond oncology. The same mechanism that allows cancer to escape immune surveillance also highlights a potential avenue for treating conditions characterized by an overactive immune response. Because the SCG2-LILRB4 interaction effectively neutralizes the immune activity of myeloid cells, delivering exogenous SCG2 could potentially dampen excessive immune responses. This opens up possibilities for novel treatments for autoimmune disorders, such as rheumatoid arthritis or lupus, and other inflammatory conditions where myeloid cells play a detrimental role.
"Conversely, 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," Dr. Zhang noted. The research team plans to pursue both of these promising avenues in future studies, aiming to translate these fundamental discoveries into tangible clinical benefits.
A Collaborative Endeavor and Funding Landscape
This significant scientific achievement was the result of a dedicated and multidisciplinary team at UT Southwestern. Contributing researchers include 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, underscoring his significant contributions to the field. Drs. Xuewu Zhang and Xu are also recognized members of the Simmons Cancer Center, highlighting the integrated research efforts within the institution.
The research was generously supported by a robust network of funding agencies, demonstrating broad confidence in the importance of this work. 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, holding equity and licensing agreements. Dr. Alec Zhang also holds equity in and has had sponsored research agreements with Immune-Onc, reflecting potential future collaborations and commercialization pathways for these groundbreaking discoveries.
The Broader Impact: Redefining Immune Regulation
The discovery of the SCG2-LILRB4 axis represents a significant advancement in our understanding of tumor immunology and immune regulation. For decades, researchers have sought to harness the power of the immune system to fight cancer, with varying degrees of success. This finding provides a concrete molecular target and a deeper mechanistic insight into one of the most significant challenges in cancer therapy: immune evasion.
The ability of cancer cells to manipulate their microenvironment, turning immune cells from adversaries into allies, is a testament to the evolutionary sophistication of malignancy. By identifying SCG2 as the hormonal trigger and LILRB4 as the cellular receptor responsible for this subversion, Dr. Zhang’s team has provided a critical vulnerability that can now be exploited.
The implications for cancer treatment are profound. Developing therapies that block the SCG2-LILRB4 interaction could potentially unleash the full power of the immune system against a wider range of cancers, particularly those that have proven resistant to existing immunotherapies. This could involve the development of novel antibodies, small molecule inhibitors, or even engineered cells designed to interfere with this signaling pathway.
Beyond cancer, the potential for treating autoimmune and inflammatory diseases is equally exciting. Conditions where the immune system mistakenly attacks the body’s own tissues often involve dysregulated myeloid cell activity. The ability to modulate this activity through SCG2 administration could offer a much-needed therapeutic option for patients suffering from chronic and debilitating inflammatory conditions.
The scientific community will undoubtedly be closely watching the further development of these findings. The journey from basic research to clinical application is often long and arduous, but the identification of such a fundamental mechanism of immune evasion and regulation offers a beacon of hope for future therapeutic interventions. The work at UT Southwestern Medical Center represents a significant leap forward, promising to redefine how we approach not only cancer but also a spectrum of immune-mediated diseases.
