By Hendra Lukman 
Researchers at UT Southwestern Medical Center have unveiled a critical mechanism by which cancer cells evade the body’s immune system, identifying a specific hormone and its receptor on immune cells that act as a potent shield. This groundbreaking discovery, detailed in the prestigious journal Nature Immunology, not only deepens our understanding of cancer immune evasion but also illuminates promising new avenues for immunotherapy, as well as potential treatments for debilitating inflammatory and neurological conditions.
The study, co-led by Professor Cheng Cheng "Alec" Zhang, Ph.D., of Physiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and postdoctoral researcher Xing Yang, Ph.D., pinpoints a surprising role for the hormone SCG2 and its interaction with the LILRB4 receptor on myeloid cells. Myeloid cells, a crucial component of the innate immune system, are typically among the first responders to tumor sites, tasked with identifying and neutralizing cancerous threats. However, the UT Southwestern findings suggest that under the influence of SCG2, these once-vigilant cells can be co-opted into becoming active accomplices of the tumor, actively suppressing the very immune responses needed to eliminate it.
"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 paradigm shift in understanding the function of myeloid cells in the tumor microenvironment represents a significant leap forward in cancer research.
The Imperfect Landscape of Cancer Immunotherapy
The development of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized cancer treatment in recent years. These therapies aim to "release the brakes" on the immune system, allowing T cells to recognize and attack cancer cells. However, their efficacy remains limited, with current treatments benefiting only an estimated 20% to 30% of patients. This statistic underscores the intricate and multifaceted strategies cancer employs to evade immune detection and destruction.
"Current immunotherapies, such as immune checkpoint inhibitors, are effective for only about 20%-30% of cancer patients," Dr. Zhang noted, highlighting the urgent need to uncover alternative mechanisms of immune evasion. "This suggests that there are multiple ways that cancers evade attack from the immune system." The discovery of the SCG2-LILRB4 pathway provides a compelling new explanation for a significant portion of these treatment failures.
A Journey of Discovery: From Inhibitory Receptor to Hormonal Culprit
The foundation of this research was laid several years ago within the Zhang Lab, where investigators were meticulously studying the complex behavior of myeloid cells in the context of cancer. During this research, they identified an inhibitory receptor on these immune cells, known as LILRB4. Their initial observations revealed that when LILRB4 was stimulated, it effectively neutralized the ability of myeloid cells to mount an anti-tumor response. This finding alone presented a puzzle: what triggers this crucial inhibitory receptor?
Driven by this question, Dr. Zhang, Dr. Yang, and their colleagues embarked on a comprehensive, genome-wide screening process. Their objective was to identify any and all proteins that might have the potential to interact with LILRB4. This exhaustive search yielded a particularly promising candidate: a hormone designated SCG2. While SCG2 had been previously implicated in various immune responses, its precise function and its specific cellular receptor remained elusive until this study.
Subsequent laboratory experiments provided definitive proof. The research team confirmed that SCG2 directly binds to the LILRB4 receptor. This binding event initiates a cascade of intracellular signaling events within the myeloid cell. The net effect of this signaling cascade is the shutdown of the myeloid cell’s anti-cancer functions. Crucially, it also impairs their ability to signal for and recruit cancer-fighting T cells to the tumor site, effectively creating a protective barrier around the malignancy.
Pre-clinical Validation: Animal Models Illuminate the Mechanism
To validate these findings in a more complex biological system, the researchers turned to pre-clinical models. They utilized mice that were genetically engineered to express the human form of the LILRB4 receptor. In these mice, when cancer cells engineered to produce SCG2 were introduced, they exhibited rapid and aggressive tumor growth. This observation strongly correlated the presence of SCG2 with accelerated tumor progression in a LILRB4-expressing environment.
The therapeutic potential of targeting this newly identified pathway was then tested. The researchers administered an antibody designed to block the LILRB4 receptor in these mice. The results were significant: treatment with the LILRB4-blocking antibody markedly slowed the growth of the tumors. In parallel experiments, the team explored the impact of directly removing SCG2 from the animals’ systems. Artificially depleting SCG2 also led to a substantial reduction in tumor growth, further reinforcing the critical role of the SCG2-LILRB4 axis in promoting cancer progression.
These pre-clinical experiments provided compelling evidence that the interaction between SCG2 and LILRB4 creates a permissive environment for cancer to flourish, effectively shielding it from the surveillance and attack of myeloid cells, T cells, and potentially other immune cell populations.
Implications for Future Therapies: A Dual-Edged Sword
The implications of this discovery are far-reaching, offering potential therapeutic strategies for both cancer and other immune-related disorders.
New Frontiers in Cancer Immunotherapy
Dr. Zhang posited that disrupting the SCG2-LILRB4 interaction could represent a novel and potent immunotherapy approach for cancer. By developing agents that block either SCG2 from binding to LILRB4 or directly inhibit the LILRB4 receptor itself, clinicians could potentially reactivate the dormant anti-tumor functions of myeloid cells and enhance the recruitment of cancer-killing T cells. This could be particularly beneficial for patients who do not respond to current immunotherapies, offering a new lifeline in their fight against the disease. The development of such targeted therapies would likely involve antibody-based treatments or small molecule inhibitors, building upon the success demonstrated in the mouse models.
A Novel Approach to Inflammatory and Neurologic Diseases
Conversely, the very mechanism that cancer exploits to evade immunity could be harnessed for therapeutic benefit in other conditions. The SCG2-LILRB4 pathway’s ability to neutralize the immune activity of myeloid cells, which are often implicated in the pathogenesis of autoimmune and inflammatory disorders, presents an intriguing therapeutic target. By delivering exogenous SCG2 or agents that mimic its action, it might be possible to dampen excessive immune responses that drive conditions such as rheumatoid arthritis, inflammatory bowel disease, or even certain neurodegenerative diseases where myeloid cell activation plays 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 explained. This dual-pronged therapeutic potential underscores the profound impact of understanding fundamental biological pathways.
A Collaborative Endeavor and Future Directions
This significant scientific achievement was the result of a multidisciplinary effort involving a distinguished team of researchers at UT Southwestern. Beyond Dr. Zhang and Dr. Yang, key contributors 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 fellow postdoctoral researchers Meng Fang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D.
Dr. Alec Zhang holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. Drs. Xuewu Zhang and Xu are also integral members of the Simmons Cancer Center, underscoring the institution’s commitment to advancing cancer research.
The research was generously supported by grants from several leading funding bodies, 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 diverse funding portfolio reflects the broad scientific interest and potential impact of the study.
It is also noteworthy that The University of Texas has a financial interest in Immune-Onc Therapeutics Inc. in the form of equity and licensing agreements. Dr. Alec Zhang personally holds equity in and has had sponsored research agreements with Immune-Onc Therapeutics Inc. This financial disclosure is standard practice and highlights the translational potential of the research.
Looking ahead, Dr. Zhang and his colleagues are poised to delve deeper into both proposed therapeutic avenues. Future studies will focus on developing and testing specific interventions aimed at modulating the SCG2-LILRB4 pathway for the treatment of cancer and inflammatory diseases. This pioneering work not only expands our fundamental knowledge of the immune system’s intricate dance with cancer but also paves the way for a new generation of targeted therapies that could profoundly impact human health. The journey from identifying a molecular interaction to developing life-saving treatments is often long, but discoveries like this mark critical milestones, offering tangible hope for patients and fueling continued scientific innovation.