Oncogene Initiates Cancer Development through Immune Checkpoints

Photo credit: Stanford University

Dean W. Felsher, M.D., Ph.D., at Stanford University School of Medicine, is an expert on oncogenes—genes that, when mutated, provide cells with the signal to divide uncontrollably. Oncogenes are a hallmark of cancer, without which cancer cannot thrive. One example is MYC, an oncogene that is commonly mutated in many different types of cancers. MYC has been recognized as master regulator of cellular proliferation, metabolism, death, and self-renewal, and its permanent activation is one of the primary causes of cancer development and progression. Previously, Dr. Felsher found that the inactivation of MYC can be sufficient to induce cancer regression, and this tumor regression depended upon the immune system, particularly CD4+ T cells.

Under his CRI Clinic and Laboratory Integration Program (CLIP) award, Dr. Felsher has sought to show that certain oncogenes regulate the expression of key immune regulatory molecules. Until now, it wasn’t known if an oncogene had any effect on these proteins.

In a paper published today in Science, Dr. Felsher found that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface—CD47, the “don’t eat me” signal in cancer cells, and PD-L1, which interact with PD-1 receptors to inhibit the immune response. MYC was found to bind directly to the promoters of CD47 and PD-L1 genes. Additionally, MYC inactivation halted CD47 and PD-L1 expression, enhancing the anti-cancer immune response.

This research has broad implications, for it suggests that the mechanisms of “oncogene-targeted drug therapy” may overlap with immunotherapy. This work could also have implications for improving the effectiveness of immune-based cancer treatments.

Hopefully future studies investigating targeted treatment and immunotherapies will reveal even more about how oncogenes use the immune system to promote tumors—as well as how it can be used to stop cancer.

Citation: MYC Regulates the Anti-Tumor Immune Response through CD47 and PD-L1. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw A, Baylot V, Guetegemann I, Eilers M, Felsher DW. Science. 2016 Mar 10.