By Hendra Lukman 
Researchers at UT Southwestern Medical Center have illuminated a critical mechanism by which cancer cells cleverly evade the body’s immune surveillance, a discovery poised to revolutionize immunotherapy and offer new therapeutic avenues for a spectrum of diseases. The groundbreaking findings, detailed in the latest issue of Nature Immunology, pinpoint a specific hormone, SCG2, and its interaction with a receptor, LILRB4, on the surface of crucial immune cells. This molecular handshake effectively disarms the immune system’s cancer-fighting capabilities, transforming what should be vigilant defenders into unwitting accomplices of tumor growth. This breakthrough holds immense promise for developing novel immunotherapies against cancer, as well as potential treatments for debilitating inflammatory and neurological disorders.
The Deceptive Dance of Myeloid Cells and Tumor Hijacking
At the forefront of the immune system’s initial response to invading pathogens and nascent tumors are myeloid cells. These frontline soldiers are designed to detect and destroy threats. However, as observed by the UT Southwestern team, a swift and insidious transformation occurs within the tumor microenvironment. Myeloid cells, upon recruitment to a tumor site, rapidly shift from being tumor-icidal to tumor-supporting.
"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 distinguished member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system." Dr. Zhang, a leading figure in the field of cancer immunology, co-led this pivotal research alongside Xing Yang, Ph.D., a postdoctoral researcher in the Zhang Lab and the study’s first author.
This complex interplay highlights a sophisticated strategy employed by cancer cells to establish and propagate. The findings directly address a significant limitation in current cancer treatment paradigms. While immunotherapies, particularly immune checkpoint inhibitors, have transformed the landscape for many patients, their efficacy remains limited, impacting only an estimated 20% to 30% of individuals diagnosed with cancer. This statistic underscores the existence of multiple, often intricate, pathways through which tumors can successfully evade immune detection and destruction. The discovery of the SCG2-LILRB4 axis offers a compelling explanation for one such evasion strategy.
A Two-Year Journey of Discovery: From Inhibitory Receptor to Hormonal Culprit
The genesis of this research can be traced back several years to earlier investigations within the Zhang Lab. At that time, researchers were meticulously examining the behavior of cancer-fighting immune cells, specifically myeloid cells. Their focus led to the identification of an inhibitory receptor on these cells, dubbed LILRB4. Crucially, they observed that stimulation of this LILRB4 receptor effectively blunted the myeloid cells’ inherent ability to mount an effective attack against tumors. This initial finding raised a critical question: what endogenous signals were activating this immunosuppressive receptor?
Driven by this inquiry, Dr. Zhang, Dr. Yang, and their colleagues embarked on a comprehensive, genome-wide screen. Their objective was to identify all cellular proteins that might interact with LILRB4. This systematic search yielded a highly promising candidate: a hormone known as SCG2 (secretogranin II). While SCG2 had been previously implicated in various biological processes, including a potential role in immune response, its precise function and its cognate receptor remained elusive.
The subsequent laboratory experiments provided definitive confirmation. The research team meticulously demonstrated that SCG2 directly binds to the LILRB4 receptor. This binding event initiates a cascade of intracellular signals. This signaling cascade, once triggered, effectively silenced the cancer-fighting machinery within myeloid cells. Furthermore, it impaired their crucial function of recruiting other potent immune cells, specifically T cells, which are essential for orchestrating a robust anti-cancer immune response, to the tumor site.
In Vivo Validation: SCG2-LILRB4 Blockade Halts Tumor Growth
To translate these in vitro findings into a more concrete understanding of their biological relevance, the researchers conducted rigorous experiments in animal models. They utilized mice that were genetically engineered to express the human form of the LILRB4 receptor. In these model systems, when cancer cells engineered to produce SCG2 were injected, they exhibited rapid and aggressive tumor growth. This observation directly mirrored the detrimental effects observed in human cancers where this pathway is active.
The therapeutic implications of this discovery were then put to the test. The research team administered an antibody specifically designed to block the LILRB4 receptor in these tumor-bearing mice. The results were striking: treatment with this blocking antibody significantly retarded tumor growth. In parallel experiments, the researchers explored the impact of artificially depleting SCG2 from the animals’ bodies. This intervention also led to a notable deceleration in cancer progression.
These complementary in vivo studies provide compelling evidence that the interaction between LILRB4 and SCG2 creates a formidable shield, enabling cancer to proliferate unchecked by the body’s natural immune defenses. This includes the compromised activity of myeloid cells, the impaired recruitment of cancer-killing T cells, and potentially the suppression of other vital immune cell populations that contribute to tumor surveillance.
Rethinking Cancer Therapy and Beyond: Therapeutic Implications
The profound implications of this discovery extend beyond the realm of cancer treatment. Dr. Zhang articulated a clear vision for how this newfound understanding could be leveraged. "Disrupting this interaction could someday offer a new immunotherapy option to treat cancer," he stated, envisioning the development of therapies that specifically target and inhibit the SCG2-LILRB4 axis. Such an approach would aim to restore the natural anti-tumor functions of myeloid and T cells, empowering the immune system to effectively recognize and eliminate cancerous cells.
Conversely, the very mechanism that fuels tumor growth also presents an opportunity 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 promising therapeutic avenues for a range of autoimmune and inflammatory disorders, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, where myeloid cells are known to play a significant role in disease pathogenesis.
Dr. Zhang and his colleagues are already planning future research to rigorously investigate both of these exciting therapeutic possibilities. Their work signifies a critical step forward in deciphering the intricate language of the immune system and its engagement with cancer and other diseases.
A Collaborative Effort: The Extended UT Southwestern Research Team
This significant scientific endeavor was not a solitary effort but rather a testament to the collaborative spirit and intellectual prowess within UT Southwestern Medical Center. The study involved a distinguished group of researchers, each contributing their unique expertise.
Among the key contributors were 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; and Lei Guo, Ph.D., a skilled Computational Biologist. Additionally, postdoctoral researchers Meng Fang, Ph.D., Chengcheng Zhang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D., played integral roles in the execution and analysis of the research.
Dr. Alec Zhang’s leadership is further recognized by his esteemed positions, including the Hortense L. and Morton H. Sanger Professorship in Oncology and his role as a Michael L. Rosenberg Scholar in Medical Research. Drs. Xuewu Zhang and Lin Xu are also recognized members of the Harold C. Simmons Comprehensive Cancer Center, underscoring the institution’s commitment to cancer research.
Funding and Institutional Interests: Sustaining Scientific Advancement
The groundbreaking research that led to this discovery was made possible through substantial financial support from a consortium of prestigious funding agencies and foundations. This includes critical grants from the National Cancer Institute (NCI), specifically R01CA248736 and R01CA263079, as well as support from the Lung Cancer 779 SPORE Development Research Program.
Further contributions came from the Cancer Prevention and Research Institute of Texas (CPRIT) through grants RP220032, RP15150551, and RP190561, highlighting the state’s dedication to advancing biomedical science. The Welch Foundation also provided essential funding through grants AU-0042-20030616 and I-1702, supporting fundamental scientific inquiry.
Additional support was received from Immune-Onc Therapeutics Inc. via a Sponsored Research Grant (No. 111077), indicating collaborative efforts between academic institutions and the biotechnology sector. The National Institutes of Health contributed through grant R35GM130289, and the NCI Cancer Center Support Grant (P30CA142543) provided overarching institutional support for cancer research at UT Southwestern.
It is noteworthy that The University of Texas holds a financial interest in Immune-Onc Therapeutics Inc., encompassing equity and licensing agreements. Dr. Alec Zhang himself holds equity in Immune-Onc and has had sponsored research agreements with the company, illustrating a potential pathway for the translation of these research findings into clinical applications. These financial connections, while common in academic research, underscore the collaborative ecosystem that fosters scientific innovation and its eventual application for public benefit. The robust and diverse funding landscape for this research underscores the significance of the findings and the confidence placed in the UT Southwestern team’s ability to advance our understanding of complex biological processes.
