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Cancer-causing gene also helps tumors dodge immune system

I've written before how oncogenes are a double-edged sword. Normally they carry out vital functions within a cell. But when they are mutated or misregulated, they can have dire effects. One well-known oncogene called Myc is known to be associated with the development of over half of all human cancers. Myc affects the expression of many genes involved in the control of cell growth and progression through the cell cycle.

Now, oncologist Dean Felsher, MD, PhD, and postdoctoral scholar Stephanie Casey, PhD, have discovered an intriguing connection between Myc and the expression of two darlings of the cancer immunotherapy world: molecules called PD-L1 and CD47 found on the surface of cancer cells. Ongoing work has shown that PD-L1 protects cancer cells from being recognized by immune cells (a kind of "don't find me" signal), while CD-47 keeps them from being destroyed (a "don't eat me" signal).

The work, published today in Science, is the first to directly link the levels of Myc, CD-47 and PD-L1, and may provide new therapeutic avenues for clinicians.

As Felsher describes in our release:

Our findings describe an intimate, causal connection between how oncogenes like Myc cause cancer and how those cancer cells manage to evade the immune system.

The researchers found that, when present at high levels, the protein encoded by the Myc oncogene binds to the DNA upstream of the PD-L1 and CD47 genes and encourages the cellular machinery to make the genes into proteins. These proteins then go to the surface of the cell to fend off any attack by the immune system. Conversely, blocking Myc expression in cancer cells reduced the amount of PD-L1 and CD47 found on the cells' surfaces. From our release:

[The researchers] found that a reduction in Myc caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human acute lymphoblastic leukemia cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells. In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.

In publicly available gene expression data on tumor samples from hundreds of patients, they found that the levels of Myc expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney and colorectal tumors.

The research suggests that targeting both Myc expression and that of CD47 or PD-L1 might provide a therapeutic synergy that would be more effective than any treatment alone. It also further highlights the importance of the immune system in battling cancer. As Felsher said:

There is a growing sense of tremendous excitement in the field of cancer immunotherapy. 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.

Previously: Smoking gun or hit-and-run? How oncogenes make good cells go badUnraveling the secrets of a common cancer-causing gene  and How cancer stem cells dodge the immune system
Image by SoundTrackUniverse

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