By Hendra Lukman 
Researchers at UT Southwestern Medical Center have made a significant breakthrough in understanding how cancer cells evade the body’s immune system, identifying a specific hormonal interaction that effectively disarms crucial immune cells. This discovery, detailed in the latest issue of Nature Immunology, unveils a novel mechanism by which cancer cells suppress anti-tumor immunity. The findings hold substantial promise for the development of next-generation immunotherapies targeting a wide range of cancers, and potentially for new therapeutic strategies for inflammatory and neurological disorders.
The study, co-led by Professor of Physiology Cheng Cheng "Alec" Zhang, Ph.D., and postdoctoral researcher Xing Yang, Ph.D., both affiliated with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, pinpoints a hormone and its receptor on the surface of myeloid cells. Myeloid cells are a critical component of the innate immune system, often among the first responders to sites of infection or injury, including nascent tumors. However, the research indicates that in the tumor microenvironment, these cells can be perverted from their tumor-fighting roles into tumor-supporting allies.
"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 suppression is particularly concerning given the limitations of current cancer treatment modalities. For instance, a cornerstone of modern cancer immunotherapy, immune checkpoint inhibitors, have demonstrated remarkable success in a subset of patients, typically benefiting between 20% to 30% of those treated. Dr. Zhang highlighted this statistic as evidence that cancers employ diverse and sophisticated strategies to evade immune detection and destruction. The newly identified mechanism represents another significant pathway through which this immune evasion occurs.
Unraveling the LILRB4-SCG2 Axis
The journey to this discovery began several years prior within the Zhang Lab, where researchers were investigating the complex interplay of immune cells within tumors. Their focus was on myeloid cells, and during this research, they identified an inhibitory receptor on these cells known as LILRB4 (Leukocyte immunoglobulin-like receptor B4). Crucially, they observed that when this receptor was stimulated, it effectively dampened the myeloid cells’ ability to engage and eliminate tumor cells. This early observation laid the groundwork for understanding a potential "off switch" for anti-cancer immunity within these critical immune players.
Following this initial identification, Dr. Zhang, Dr. Yang, and their colleagues embarked on a comprehensive investigation to identify the specific molecular partners that interact with LILRB4. They employed a genome-wide screening approach, systematically examining all proteins that could potentially bind to and modulate the function of LILRB4. Among the candidates that emerged as particularly promising was a hormone known as SCG2 (secretogranin II).
While SCG2 had been previously implicated in various physiological processes, including potential roles in immune responses, its precise function and cellular receptor had remained largely elusive. The UT Southwestern team’s laboratory experiments provided the definitive link: SCG2 was confirmed to bind directly to the LILRB4 receptor. This binding event initiates a cascade of intracellular signaling within the myeloid cells. The net effect of this signaling cascade is a profound suppression of the myeloid cells’ anti-tumor capabilities. Furthermore, this interaction impairs the myeloid cells’ ability to orchestrate a broader immune response by hindering their capacity to attract and activate cancer-fighting T cells, which are the primary effectors of adaptive immunity against cancer.
Pre-clinical Validation in Mouse Models
To validate their findings in a living system, the researchers utilized sophisticated mouse models. They employed mice that were genetically engineered to express the human form of LILRB4, ensuring that the interactions they observed were relevant to human biology. In these mice, when cancer cells engineered to produce SCG2 were injected, they exhibited rapid and aggressive tumor growth. This observation strongly suggested that the SCG2-LILRB4 axis directly facilitated tumor progression by neutralizing anti-tumor immune responses.
The therapeutic implications of this discovery were further tested by intervening in this newly identified pathway. The researchers treated these tumor-bearing mice with an antibody specifically designed to block the LILRB4 receptor. The results were significant: antibody treatment substantially slowed the growth of the tumors. In parallel experiments, they also investigated the effect of artificially depleting SCG2 from the animals’ systems. This approach also led to a marked inhibition of cancer growth, further reinforcing the critical role of the SCG2-LILRB4 interaction in promoting tumor development.
These pre-clinical studies provided compelling evidence that the interaction between SCG2 and LILRB4 creates a protective shield around cancer cells, allowing them to proliferate unchecked by the body’s natural immune defenses, including myeloid cells and T cells. The potential for disrupting this pathway as a novel cancer treatment strategy emerged as a primary implication of the research.
Broader Therapeutic Horizons
The implications of this discovery extend beyond cancer treatment. Dr. Zhang noted that because the SCG2-LILRB4 interaction effectively neutralizes the immune activity of myeloid cells, manipulating this pathway could offer therapeutic benefits in conditions where excessive immune cell activity is detrimental. Specifically, delivering exogenous SCG2 or molecules that mimic its action could potentially dampen the overactive immune responses characteristic of autoimmune diseases and inflammatory disorders. In these conditions, myeloid cells can contribute to tissue damage and chronic inflammation. By inhibiting their activity, SCG2 could serve as a therapeutic agent to calm an overzealous immune system.
"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 stated. This dual-pronged therapeutic potential underscores the significance of the SCG2-LILRB4 axis as a fundamental regulator of immune homeostasis.
The researchers at UT Southwestern plan to delve deeper into both of these promising therapeutic avenues in their future studies. This includes designing and testing specific inhibitors of the SCG2-LILRB4 interaction for cancer therapy and exploring the potential of SCG2 agonists for treating inflammatory conditions.
A Collaborative Endeavor and Funding Landscape
This groundbreaking research was a collaborative effort involving a multidisciplinary team of scientists at UT Southwestern. 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., a 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 prestigious Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. Dr. Xuewu Zhang and Dr. Xu are also integral members of the Simmons Cancer Center.
The research was supported by substantial funding from a variety of national and institutional sources, reflecting the high priority placed on cancer research and immunology. Grants from the National Cancer Institute (NCI) (R01CA248736, R01CA263079, and the Lung Cancer 779 SPORE Development Research Program) provided foundational support. Additional funding 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 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 Immune-Onc and has had sponsored research agreements with the company. These disclosures ensure transparency and adherence to ethical guidelines in scientific research and its potential commercialization.
The identification of the SCG2-LILRB4 pathway represents a significant stride in our understanding of tumor immunology. It opens new avenues for therapeutic intervention, offering hope for more effective treatments for cancer patients and potential new strategies for managing debilitating inflammatory and neurological conditions. The continued investigation into this complex biological axis is poised to yield further insights and innovations in the years to come.
