Ever heard of a cancer disappearing on its own? It’s rare, but it happens, and it’s particularly interesting in a type of kidney cancer called clear cell renal cell carcinoma (ccRCC). While ccRCC doesn’t have a high number of mutations, which usually drives a strong immune response, it does sometimes spontaneously regress and often responds well to immunotherapy. This suggests our immune system can recognize and fight ccRCC, but how? That’s where things get fascinating.

The key to understanding ccRCC lies in a gene called VHL. When VHL isn’t working correctly (like a broken light switch), it causes another protein called HIF to become overactive. Think of HIF as a master control switch that turns on many other genes, some of which shouldn’t be active. This broken VHL/overactive HIF pathway is the hallmark of ccRCC.

Now, there was a remarkable case report where a patient with ccRCC was cured after an allogeneic stem cell transplant (meaning they received stem cells from a donor). Researchers discovered that the donor’s immune cells, specifically the T cells (the body’s attack dogs), recognized and destroyed the patient’s ccRCC. Further investigation revealed these T cells were targeting a specific piece of a protein produced by a “dormant” virus lurking within our DNA called an endogenous retrovirus (ERV). This particular ERV is named ERVE-4.

This discovery sparked a lot of interest in the role of ERVs in ccRCC. It turns out ERVE-4 isn’t alone. Our research shows that HIF, that master control switch we talked about, actually activates many different ERVs in ccRCC cells. These activated ERVs produce proteins, fragments of which are displayed on the surface of the cancer cells like flags, signaling to the immune system that something’s wrong. Importantly, these ERV-derived “flags” can be recognized by T cells, potentially triggering an immune attack against the cancer.

Here’s a breakdown of the key takeaways:

• VHL inactivation and HIF upregulation: The key characteristic of ccRCC is a broken VHL gene, leading to an overactive HIF protein.
• ERV activation: HIF doesn’t just turn on random genes; it also activates normally silent endogenous retroviruses (ERVs).
• Immune system recognition: These activated ERVs produce proteins that can be recognized by the immune system, specifically T cells, as foreign or dangerous.
• Potential for immunotherapy: This opens exciting possibilities for developing new immunotherapies that specifically target ERV-derived proteins in ccRCC, harnessing the power of the patient’s own immune system to fight the cancer.
• Beyond ccRCC: Interestingly, we’ve also found that we can activate ERVs in other cancer types using drugs that stabilize HIF, suggesting this approach might be applicable to a broader range of cancers.

The story of ERVs and ccRCC is a promising area of cancer research. By understanding how these “dormant” viruses can be activated and targeted by the immune system, we hope to develop more effective and personalized cancer treatments in the future. It’s an exciting time, and we’re just beginning to scratch the surface of the potential of ERVs in cancer immunotherapy.