"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. Our study suggests that receptors on these myeloid cells get stimulated by this hormone and end up suppressing the immune system," said Cheng Cheng "Alec" Zhang, Ph.D., Professor of Physiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Zhang co-led the study with first author Xing Yang, Ph.D., a postdoctoral researcher in the Zhang Lab.

Current immunotherapies, such as immune checkpoint inhibitors, are effective for only about 20%-30% of cancer patients, Dr. Zhang said, suggesting that there are multiple ways that cancers evade attack from the immune system.

Several years ago, researchers in the Zhang Lab studying cancer-fighting immune cells called myeloid cells identified an inhibitory receptor called LILRB4. Stimulating this receptor blocked the myeloid cells' ability to attack tumors.

Dr. Zhang, Dr. Yang, and their colleagues then did a genome-wide screen of all proteins that might interact with LILRB4. A promising hit was a hormone called SCG2. Although researchers have suggested that SCG2 plays a role in immune response, its function and receptor were unknown. Laboratory experiments confirmed that SCG2 binds to LILRB4, kicking off a signaling cascade that turned off the cancer-fighting abilities of myeloid cells and inhibited their ability to recruit cancer-fighting T cells to tumors.

In mice genetically altered to express the human form of LILRB4, injected cancer cells that produced SCG2 grew rapidly as tumors. Treating these mice with an antibody that blocks LILRB4 significantly slowed cancer growth, as did artificially ridding the animals' bodies of SCG2.

Together, these experiments suggest that interactions between LILRB4 and SCG2 allow cancer to grow unchecked by myeloid cells, T cells, and potentially other immune cell types. Dr. Zhang suggested that disrupting this interaction could someday offer a new immunotherapy option to treat cancer. 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 and his colleagues plan to investigate both ideas in future studies.

Other UTSW researchers who contributed to this study 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 Meng Fang, Ph.D., Chengcheng Zhang, Ph.D., Ankit Gupta, Ph.D., and Lianqi Chen, Ph.D., postdoctoral researchers.

Dr. Alec Zhang holds the 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 members of the Simmons Cancer Center.

This study was funded by grants from 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 NCI Cancer Center Support Grant (P30CA142543).

The University of Texas has a financial interest in Immune-Onc in the form of equity and licensing. Dr. Alec Zhang holds equity in and had sponsored research agreements with Immune-Onc.