By Hendra Lukman 
Researchers at UT Southwestern Medical Center have illuminated a critical molecular pathway through which cancer cells subvert the body’s immune defenses, a discovery published in the prestigious journal Nature Immunology. The groundbreaking findings detail how a specific hormone, SCG2, interacts with a receptor, LILRB4, on the surface of myeloid cells, effectively transforming these crucial immune sentinels into facilitators of tumor growth. This revelation not only deepens our understanding of cancer’s evasive strategies but also presents a promising dual-pronged approach for novel cancer immunotherapies, as well as potential treatments for a spectrum of inflammatory and neurological conditions.
The Unseen Alliance: Hormone SCG2 and LILRB4 Receptor
At the heart of this discovery lies the intricate interplay between SCG2 and LILRB4. Myeloid cells, a diverse group of immune cells, are typically among the first responders to the presence of tumors. Their role is to identify and neutralize cancerous cells. However, as this new research indicates, tumors possess a sophisticated mechanism to co-opt these very cells.
"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, who co-led the study. "Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system."
This suppression occurs through a specific receptor on the myeloid cells, known as LILRB4 (Leukocyte Immunoglobulin-like Receptor B4). While the role of myeloid cells in cancer immunity has been a focus of intense research, the precise mechanisms by which tumors inhibit their activity have remained partially obscured. The identification of LILRB4 as a key inhibitory receptor several years ago by the Zhang Lab provided a crucial piece of the puzzle. Experiments at that time demonstrated that stimulating LILRB4 effectively crippled the myeloid cells’ ability to combat tumors.
The subsequent challenge was to identify the specific molecular trigger that activates LILRB4. This led Dr. Zhang, along with first author Xing Yang, Ph.D., a postdoctoral researcher in the Zhang Lab, and their colleagues, to embark on a comprehensive, genome-wide screen of all proteins that might interact with LILRB4. This meticulous search yielded a significant finding: the hormone SCG2 (Secretogranin-II).
While SCG2 had previously been implicated in various physiological processes, including immune responses, its specific function and cellular receptor had remained largely undefined. The UT Southwestern team’s laboratory experiments provided definitive confirmation. They demonstrated that SCG2 directly binds to LILRB4. This binding initiates a cascade of intracellular signals within the myeloid cells, effectively shutting down their anti-cancer functions. Crucially, this signaling also impedes the myeloid cells’ ability to recruit other potent cancer-fighting immune cells, such as T cells, to the tumor site.
From Laboratory Bench to Clinical Potential: Evidence and Implications
The implications of this molecular handshake between SCG2 and LILRB4 were further validated through in vivo studies. Researchers utilized mice genetically engineered to express the human form of LILRB4. When these mice were injected with cancer cells that were engineered to produce SCG2, the tumors exhibited rapid and aggressive growth. This observation powerfully illustrates how the SCG2-LILRB4 axis facilitates tumor progression by neutralizing the immune system’s immediate response.
The therapeutic potential of targeting this pathway became evident in subsequent experiments. Treating these tumor-bearing mice with an antibody designed to block LILRB4 significantly impeded tumor growth. Similarly, artificially reducing the levels of SCG2 in the animals’ bodies also led to a substantial slowdown in cancer progression. These findings provide compelling preclinical evidence that disrupting the SCG2-LILRB4 interaction can restore the immune system’s capacity to control tumor development.
The current landscape of cancer immunotherapy, while revolutionary, still faces limitations. Immune checkpoint inhibitors, a cornerstone of modern cancer treatment, are effective for only about 20% to 30% of patients. This statistic underscores the existence of multiple, often complex, mechanisms by which cancers evade immune surveillance. The discovery of the SCG2-LILRB4 pathway offers a novel target that could potentially overcome some of these limitations, thereby expanding the reach of immunotherapy to a broader patient population.
A Dual Therapeutic Promise: Cancer and Autoimmune Disorders
The therapeutic implications of this research extend beyond oncology. Dr. Zhang highlighted the dual nature of this discovery. "Disrupting this interaction could someday offer a new immunotherapy option to treat cancer," he stated. "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."
This latter point is particularly significant. In conditions like rheumatoid arthritis, lupus, or inflammatory bowel disease, an overactive or misdirected immune response, often involving myeloid cells, contributes to tissue damage and chronic inflammation. By leveraging the immunosuppressive properties of the SCG2-LILRB4 axis, it may be possible to dampen these harmful immune responses. Instead of blocking the interaction to unleash anti-cancer immunity, delivering exogenous SCG2 could intentionally induce localized immunosuppression, thereby alleviating inflammation and protecting healthy tissues.
The researchers plan to vigorously pursue both avenues in future studies, aiming to translate these foundational discoveries into tangible clinical benefits.
A Collaborative Effort and Funding Landscape
This significant research endeavor was a testament to extensive collaboration within UT Southwestern Medical Center. Beyond Dr. Zhang and Dr. Yang, the study benefited from the expertise of several other UTSW researchers. This 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 Meng Fang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D., who all served as postdoctoral researchers.
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, highlighting his significant contributions to the field. Dr. Xuewu Zhang and Dr. Xu are also recognized members of the Simmons Cancer Center, underscoring the institutional commitment to advancing cancer research.
The funding for this multifaceted research was substantial, reflecting the critical importance of the work. Grants were provided by the National Cancer Institute (NCI) with specific awards R01CA248736 and R01CA263079, as well as the Lung Cancer 779 SPORE Development Research Program. Additional support came from the Cancer Prevention and Research Institute of Texas (RP220032, RP15150551, RP190561), The Welch Foundation (AU-0042-20030616, I-1702), Immune-Onc Therapeutics Inc. through a 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 himself holds equity in and has had sponsored research agreements with Immune-Onc, indicating potential avenues for further development and commercialization of these findings.
Broader Impact and Future Directions
The identification of the SCG2-LILRB4 axis represents a significant leap forward in our understanding of tumor immunology. It provides a concrete molecular mechanism that explains how some of the body’s own immune cells can be subverted to protect cancer. This insight is critical for developing more effective and targeted therapies.
The implications for cancer treatment are profound. The development of drugs that specifically block the SCG2-LILRB4 interaction could offer a new class of immunotherapies. These could potentially be used alone or in combination with existing treatments, such as immune checkpoint inhibitors or chemotherapy, to enhance the body’s ability to fight cancer. The preclinical data suggests that such a blockade could significantly reduce tumor burden and improve patient outcomes.
Furthermore, the potential to use SCG2 as a therapeutic agent for inflammatory and autoimmune diseases opens up an entirely new frontier. By carefully modulating the immune response, it may be possible to treat a range of debilitating conditions with greater precision and fewer side effects than current treatments.
The journey from basic scientific discovery to clinical application is often long and complex. However, the robust findings from the UT Southwestern team provide a solid foundation for future research and development. The ongoing investigations by Dr. Zhang and his colleagues will be crucial in determining the ultimate clinical utility of targeting the SCG2-LILRB4 pathway, potentially ushering in a new era of therapeutic innovation for both cancer and a variety of immune-mediated diseases.