Researchers from Boston University Chobanian & Avedisian School of Medicine have discovered that the signaling molecule chemokine-like factor (CKLF) plays a key role in promoting immunosuppression and tumor aggression in neuroblastoma and potentially in other tumors with abnormal activation of the MYCN oncoprotein.
“The MYCN oncoprotein drives the initiation, progression, and treatment resistance of a broad spectrum of human cancers,” explain Hui Feng, associate professor of pharmacology, physiology & biophysics at the school, and co-authors in Science Advances.
They say that solid tumors with aberrant MYCN activation, particularly high-risk neuroblastoma, are immunologically “cold,” characterized by a low mutational burden and few tumor-infiltrating lymphocytes, particularly cytotoxic CD8+ cells, and respond poorly to immunotherapy.
“As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness,” said Feng. “Understanding how tumor cells utilize the CKLF 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.”
Neuroblastoma is the most common extracranial solid tumor among children, and increased MYCN activity contributes to approximately 50% of high-risk disease. Patients with MYCN-driven neuroblastoma typically have a 5-year survival rate of just 40%, and there is a clear unmet medical need for effective treatments for these individuals.
To address this need and better understand mechanisms of MYCN-mediated immunosuppression, Feng and team carried out a series of studies in patient samples, cell culture, and in a zebrafish model of neuroblastoma.
They first showed that CKLF was the most highly expressed chemokine – molecules that tumors often secrete to influence the movement and dynamics of immune cells – across 84 types of solid tumors. Moreover, elevated CKLF expression was significantly associated with poor patient survival in immunologically cold tumors including neuroblastoma, glioma, hepatocellular carcinoma, and renal clear cell carcinoma.
They then found that higher CKLF expression in neuroblastoma was associated with MYCN amplification, high-risk disease, advanced disease stage, and older patient age. Conversely, levels of the second and third most highly expressed chemokines – CXCL16 and CXCL1 – were not associated with survival in patients with neuroblastoma.
Using the zebrafish model of MYCN-driven high-risk neuroblastoma, the investigators demonstrated that, as early as the premalignant stage, tumor cells secrete CKLF to recruit CD4+ immune cells in the tumor microenvironment, leading to immunosuppression and tumor aggression.
Feng told Inside Precision Medicine that the data suggest that “CKLF inhibition could evoke the body’s immune system to fight cancer more effectively and thus enhance immunotherapy.”
However, further studies are needed to validate this hypothesis and determine whether the approach is feasible and non-toxic, given that non-tumor cells can also express CKLF.
Feng concludes: “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.”
