New Cancer Immunotherapy Activates Necroptosis Mechanisms

While traditional chemo- and radiotherapeutic interventions are effective in reducing tumor size, they unfortunately also affect healthy cells. For decades, scientists have known that the immune system is a more accurate weapon that has evolved to recognize and eliminate disease-causing cells.

However, until recently researchers have had difficulties activating the immune system to recognize tumors, as cancer cells employ a range of different strategies to confuse and thwart the immune system. The recent rise of immunotherapies, which help stimulate the immune system to better identify specific cancer cells, show promising results but are still in need of a great deal of improvement.

Now, investigators at the VIB-UGent Center for Medical Biotechnology have taken important steps toward the development of cancer-targeting immunotherapy. The research team developed a treatment in mice that destroys part of the tumor and stimulates the immune system to attack persistent surviving cancer cells.

Also, the researchers demonstrated that the treatment protects against the development of tumor formation in other areas of the body. Findings from the new study were published in Nature Communications through an article titled “Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes.”

“We developed an immune therapy that causes part of the cancer cells to produce MLKL [mixed lineage kinase domain-like],” explains Lien Van Hoecke, a doctoral candidate at the VIB-UGent Center for Medical Biotechnology. “As a result, these cancer cells die. The dead cells then activate the immune system, which attacks tumor cells that survived the initial treatment.”

In this study, the researchers sought to enhance immunotherapy approaches in an inventive way by provoking a certain type of cell death, called necroptosis, in cancer cells. Previous research has demonstrated that when cells die from necroptosis, the immune system is alarmed.

“This phenomenon is also called immunogenic cell death, as the dying cells become examples for the immune system, which then learns and remembers which cells to search for an attack,”  Van Hoeck notes.

Building on that knowledge, the team went looking for a way to provoke necroptosis in cancer cells and thus “teach” the immune system how to attack tumors. The researchers explored MLKL, a protein that plays a crucial role in necroptosis, for their research goal.

“We describe a generic antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner MLKL protein,” the authors wrote. “This intervention stalls primary tumor growth and protects against distal and disseminated tumor formation in syngeneic mouse melanoma and colon carcinoma models. Moreover, MLKL-mRNA treatment combined with immune checkpoint blockade further improves the antitumor activity. MLKL-mRNA treatment rapidly induces T cell responses directed against tumor neo-antigens and requires CD4⁺ and CD8⁺ T cells to prevent tumor growth.”

“Our treatment not only inhibits primary tumor growth in mice but also provides protection against untreated tumors and disseminated tumors,” concludes senior study investigator Xavier Saelens, Ph.D., a professor at the VIB-UGent Center for Medical Biotechnology. “This is because the immune system is able to recognize cancer cells located in other areas of the body after confronting destroyed cells in the treated tumor. The outcomes of our study open up a number of avenues for the application of this therapy in humans.”