Vaccine Shows Cancer Cells May Succumb to Induced Necroptosis, Not Just Apoptosis

    Some of the most promising experimental cancer therapies have been exploiting immunogenic cell death, a means of heightening the immune system’s ability to attack tumors. To date, immunogenic cell death has been induced by means of apoptosis, a kind of programmed cell death. Meanwhile, another cell death mechanism, necroptosis, has remained relatively unexplored. But now that a new study has shown that necroptotic cancer cells can serve as an anticancer vaccine, the necroptosis path may become increasingly familiar.

    That’s the hope of researchers based at the University of Ghent. They assert, on the basis of experiments with necroptotic cancer cells, that necroptosis, like apoptosis, can be highly immunogenic. They add that their findings could open novel perspectives for the use of necroptosis as a part of cancer immunotherapy.

    The findings appeared March 31 in the journal Cell Reports, in an article entitled, “Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity.” This article notes that tumors are often resistant to apoptosis. Accordingly, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. And so the researchers developed a genetic model that could promote necroptosis. In this model, direct dimerization of the Fas-associated death domain protein, FADD, was combined with inducible expression of RIPK3.

    “We report that necroptotic cancer cells release damage-associated molecular patterns and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation,” wrote the authors. “Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells.”

    Every second, one million cells die by programmed cell death in a healthy human body. Immune cells efficiently clear the body from these dying cells without eliciting an inflammatory response. Elimination of cancer cells by induction of cell death is also one of the main goals in anticancer therapy, resulting in the reduction of tumor mass. In the past decade, a number of anticancer drugs have been described to not only kill the cancer cells, but also to elicit an immune response in the patient—a phenomenon referred to as immunogenic cell death.

    To date, this type of immunogenic cell death has been described only for programmed cell death elicited by a number of cancer drugs. At the University of Ghent, Ph.D. student Tania Løve Aaes and Dr. Dmitri V. Krysko, under the guidance of Prof. Dr. Peter Vandenabeele, show that another type of regulated cell death program termed necroptosis is also highly immunogenic.

    “In our research, we developed a system that can elicit necroptosis in cancer cells,” explained Ases. “We administered these killed cancer cells in mice and found that they have a clear protective effect against tumour growth. We are now studying the findings in other relevant tumor models.”

    “Many cancer cells develop resistance to the induction of cell death by apoptotic pathways,” added Prof. Vandenabeele. “With this research we hope to provide an alternative way to kill cancer cells by inducing another type of immunogenic cell death, that is necroptosis, to kill cancer cells and to elicit a specific anti-cancer immune response. These results could pave the way for necroptosis as a novel target in cancer immunotherapy.”