Stanford University School of Medicine researchers shed light on how oncogenes participate in the genesis and progression of cancer, helping tumor cells evade immune responses. The team studied the Myc oncogene and found that this protein directly controls two molecules within tumor cell surfaces that are essential for tumor progression and the evasion of immune defenses.
The research paper, titled “MYC regulates the antitumor immune response through CD47 and PD-L1,” was published in Science.
Oncogenes normally perform vital functions in cells, but when mutated or expressed in abnormal levels their activity promotes the development and progression of cancers. Myc oncogene is mutated in many human cancers, causing the encoded transcription factor Myc to be overexpressed. Previous research has shown that blocking the expression of the Myc gene leads to the regression of certain tumors in animals, a phenomenon known as oncogene addiction as the tumor is dependent on its expression. Because this regression was shown to only occur in animals with intact immune systems, researchers theorized that a relationship exists between Myc and the immune system.
Researchers investigated the possible link between Myc and the innate immune regulator Cluster of Differentiation 47 (CD47) and the adaptive immune checkpoint programmed death-ligand 1 (PD-L1). CD47 is a protein overexpressed in almost all human cancers, sending signals that protect cancer cells from being “eaten” by macrophages. PD-L1 is known to suppress the immune system during cancer and autoimmune diseases, and is also overexpressed in many cancers. Myc was found to regulate the expression of both molecules.
Suppression of Myc in mouse and human tumors, such as acute lymphoblastic leukemia (ALL) and liver cancer, was accompanied by a reduction of CD47 and PD-L1 mRNA and protein levels, while other immune regulatory molecules remained unaffected. The researchers also analysed available genetic data from patients, and found that the levels of Myc expression were strongly correlated with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors. Moreover, Myc was found to bind directly to the promoter regions of the CD47 and PD-L1 genes, an interaction that raised the levels of CD-47 expression in a human blood cell line. The inactivation of Myc in mouse models of cancer led to the lower expression of CD47 and PD-L1, enhancing the anti-tumor immune response. But when scientists engineered mouse leukemia cells to constantly express CD-47 and PD-L1 genes, regardless of Myc status, the cells were able to effectively evade immune system cells (macrophages and T-cells). Importantly, tumors derived from these cells continued to grow and did not regress when Myc was shut down.
Researchers believe that a synergetic therapy, combining the targeting of Myc, Pd-L1 and CD47, could have an enhanced effect on anti-tumor activity, slowing or stopping its growth while alerting the immune system.
“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Professor Dean Felsher, MD, the study’s senior author, said in a press release. “In many cases, it’s working. But it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”
