Wistar Institute Researchers Discover Parkinson-Linked Protein’s Role in Cancer and T Cell Activation
The Wistar Institute’s President and CEO, Dario C. Altieri, M.D., and his team have uncovered the role of Parkin—a protein associated with Parkinson’s disease—in the body’s innate immune response to cancer. They found that Parkin is not expressed in various cancers. By engineering cancer cells to re-express Parkin, they demonstrated that it enhances the production of interferons, which activate and recruit T cells to combat tumors. Their findings are detailed in The Journal of Clinical Investigation in the study titled “Parkin activates innate immunity and promotes anti-tumor immune responses.”
“Parkin’s connection to cancer has only recently come to light, and our research contributes to understanding this relationship. We are the first to show its dual role in inhibiting tumor characteristics while activating innate immunity,” said Altieri, who is also the director of the Ellen and Ronald Caplan Cancer Center and the Robert & Penny Fox Distinguished Professor at The Wistar Institute.
Parkin is known for its function in degrading damaged and surplus proteins, with the loss of its expression due to genetic mutations in the PRKN gene being primarily linked to Parkinson’s disease. However, Parkin can also be epigenetically silenced in several cancers, including lung, ovarian, and breast cancer.
Epigenetic silencing occurs when physical changes to the genome prevent specific genes from being expressed or translated into proteins. In the case of Parkin, this silencing is mediated through DNA methylation, where methyl groups are added to DNA. To explore the relationship between Parkin and cancer cells, Altieri and an international team of collaborators reintroduced Parkin into tumor cells both in vitro and in vivo.
Their research revealed that the presence of Parkin led to the production of interferons—a group of cytokine proteins crucial for immune responses. In an in vivo experiment, they restored PRKN expression in mice using the approved demethylating agent decitabine, which removes the gene-silencing methyl groups from DNA. This treatment effectively restored Parkin expression and slowed tumor growth.
By stimulating interferon production—a key component of the immune response—the team found that Parkin’s activation ultimately attracted anti-cancer T cells, which contributed to tumor suppression. To validate this mechanism, the researchers expressed Parkin while inhibiting interferon signaling and also in immunocompromised mice. In both cases, the tumor-suppressive effects were negated, proving that the immune system’s response is vital for Parkin’s role in reducing tumors.
“We are thrilled to reveal a new mechanism of interaction between the immune system and tumor cells, as we can only treat what we understand,” said Michela Perego, Ph.D., the study’s first author. “Reactivating Parkin could lead to new treatment options and enhance the immune system’s ability to combat cancer.”