(Boston)—The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy—a treatment that uses the body's immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.
In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness.
"As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness. Understanding how tumor cells utilize this molecule to communicate with immune cells will facilitate the development of effective immunotherapeutic strategies to provide more effective treatments with fewer toxicities for children with high-risk neuroblastoma," explained corresponding author Hui Feng, MD, PhD, associate professor of pharmacology, physiology & biophysics at the school.
The researchers studied an experimental model, clinical patient samples, and in-vitro cell culture. The experimental models of neuroblastoma with and without overexpression of the signaling molecule, CKLF, were compared for their ability to increase tumor aggression through the suppression of anti-tumor immune responses.
According to Xiaodan Qin, PhD, the first author of the study and a research scientist in the Feng Lab, the research is critical to understanding the mechanisms by which tumor cells induce a tumor microenvironment that compromises the function of immune cells, and it uncovered additional therapeutic approaches to evoke anti-tumor immune responses. "The long-term goal of this research is to uncover effective drugs that are much less toxic than chemotherapy and radiotherapy for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancers," Feng says.
The findings appear online in Science Advances.
Funding for this study was provided by grants from the National Institutes of Health (NIH: CA134743 and CA215059), the St. Baldrick's Foundation, the National Science Foundation (1911253), the American Cancer Society (RSG-17-204-01-TBG), and the Alex's Lemonade Stand Foundation to H.F; X.Q. is supported by a Warren Alpert Distinguished Scholars Fellowship; X.Z. is supported by a postdoctoral fellowship from the China Scholarship Council (No. 201808440648). S.S. is supported by a Young Investigator Award from the Rally Foundation for Childhood Cancer Research and the Friends for Life Neuroblastoma Fellowship. J.B.I. acknowledges support from the NIH (K12CA090354) and Conquer Cancer Foundation. A.F. and K.S. are supported by the Undergraduate Research Opportunity Program from Boston University. H.N. received the support through a POST award from the Alex's Lemonade Stand Foundation. D.B.K. is supported by a grant from the NIH (R01HL157174). R.E.G. acknowledges support from the St Baldrick's Foundation, a DoD Idea Award (CA191000), and an NIH grant (R01CA271605). The Dana-Farber/Harvard Cancer Center is
supported in part by an NCI Cancer Center Support 39 Grant (NIH P30CA06516).
