Scientists found that dormant viral genes can be reactivated in kidney cancer, prompting an immune response, offering new potential for immunotherapy.
Dana-Farber researchers have discovered that in clear cell renal cell carcinoma, the most common type of kidney cancer, dormant viral genes embedded in the human genome can become reactivated. Once activated, these genes produce viral proteins that can trigger the immune system to recognize and attack the cancer.
These viral genes are remnants of ancient viral infections that became part of human DNA over evolutionary time. Although most remain inactive, some can be reawakened under specific conditions, leading to the production of viral-like 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.
Stimulating an Immune Attack
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.
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.
Reference: “HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy” by Qinqin Jiang, David A. Braun, Karl R. Clauser, Vijyendra Ramesh, Nitin H. Shirole, Joseph E. Duke-Cohan, Nancy Nabilsi, Nicholas J. Kramer, Cleo Forman, Isabelle E. Lippincott, Susan Klaeger, Kshiti M. Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P. Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, Yijia Jiang, Rong Li, Sudeepa Syamala, Suzanna Rachimi, Eva K. Verzani, Jonathan D. Stevens, William J. Lane, Sabrina Y. Camp, Kevin Meli, Melissa B. Pappalardi, Zachary T. Herbert, Xintao Qiu, Paloma Cejas, Henry W. Long, Sachet A. Shukla, Eliezer M. Van Allen, Toni K. Choueiri, L. Stirling Churchman, Jennifer G. Abelin, Cagan Gurer, Gavin MacBeath, Richard W. Childs, Steven A. Carr, Derin B. Keskin, Catherine J. Wu and William G. Kaelin, 28 February 2025, Cell.
DOI: 10.1016/j.cell.2025.01.046
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
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