Study Title: HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy
Publication: Cell - February 28, 2025, 11:00am ET
Dana-Farber Cancer Institute corresponding authors: Derin B. Keskin, PhD, Catherine J. Wu, MD, William G. Kaelin Jr., MD
Summary:
Dana-Farber investigators found that normally defunct viral genes that lie dormant in the human genome can be activated in the most common form of kidney cancer (clear cell renal cell carcinoma) and can end up triggering an immune response against the cancer. The human genome contains viral DNA that was integrated into the genomic code long ago. A subset of these viral genes can still be reactivated under certain circumstances to produce viral proteins. This study showed that when the tumor suppressor gene VHL is inactivated by a mutation - a hallmark of clear cell renal cell cancer cells - these viruses in our genome (called endogenous retroviruses) are more likely to produce their proteins and that this process is driven by a human protein called HIF2, which is overabundant when VHL is crippled. The team also found that the cancer cells break these viral proteins into fragments and present them on the cell surface as flags that have the potential to stimulate an immune response. Additional tests in human samples and in mice suggest that these flags can be detected by the immune cells called T cells and do stimulate an immune response against the cancer.
Significance:
Evidence suggests that kidney cancer, unlike most other forms of cancer, is sometimes eradicated by the immune system. Exactly how is not well understood. This study suggests that the immune system can mount an attack on cancer cells that, due to the presence of cancer-driving mutations, present fragments of endogenous retroviral proteins on their surface. The discovery points to the potential for investigating new ways to leverage endogenous retroviruses in the development of novel immunotherapies.
Funding:
The U.S. Department of Defense, the National Institutes of Health, Howard Hughes Medical Institute, Breast Cancer Research Foundation, Louis Goodman and Alfred Gilman, the Yale Cancer Center, Swiss National Science Foundation, the Kohlberg Chair at Harvard Medical School, the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, the Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Breast Cancer Research Foundation.
