New research
suggests that inducing a form of controlled cell death called necroptosis in or
around tumor cells can help the immune system rid the body of cancer cells.

What is Necroptosis

Necroptosis
is an explosive form of cell death during which a cell typically swells and
then bursts. In the study, researchers found that injecting cells undergoing
necroptosis into tumors in mice kickstarted an immune response against the
tumors.

In the
NCI-funded study, published June 21 in Science Immunology, the researchers also
used a virus to deliver genes for the proteins that drive necroptosis into
tumor cells. Combining this treatment with a commonly used form of
immunotherapy proved to be highly effective at eliminating tumors in mice, they
reported.

Immunologist
Andrew Oberst led the project

Andrew
Oberst, Ph.D., an immunologist at the University of Washington, who led the
project, sees these as pilot experiments. “The findings are promising in
thinking about how necroptosis could be deployed in the clinic someday, after
significant additional development.”

Testing
Necroptosis in Mice

The body
uses several different methods of cell death to rid itself of abnormal,
harmful, or unneeded cells. Researchers believe necroptosis is the body’s
method of killing cells infected by viruses, Dr. Oberst explained. Necroptotic
cells flood the area around infected cells with small signaling molecules
called cytokines that can trigger inflammation and attract immune cells.

“The kind of
immune response that happens with viral infections is also the response cancer
immunotherapy tries to trigger, so we hoped that necroptosis would stimulate
some of those same pathways to help clear the body of cancer cells,” he added.

“Any cancer
treatment is aimed at killing cancer cells, but how cells die is important,”
explained Konstantin Salnikow, Ph.D., a program director in NCI’s Division of
Cancer Biology. In order to eliminate cancer cells from the body more
effectively, “we need to move toward cancer treatments that provoke an immune
response,” Dr. Salnikow said.

To start,
Dr. Oberst’s team had to see if inducing necroptosis would help the immune
system fight cancer cells. They knew from past studies that to start
necroptosis they had to activate the protein kinase RIPK3, which works with
other proteins in the cell to start the process of self execution.

Annelise
Snyder, Ph.D., then a graduate student in Dr. Oberst’s lab, activated RIPK3
protein in tumor cells to make them necroptotic. She then injected the
engineered necroptotic cells into either melanoma or adenocarcinoma tumors
implanted under the skin of mice. The necroptotic cells slowed down tumor
growth and helped the mice live longer than when Dr. Snyder injected apoptotic
cells into the tumors. Apoptosis is a tidier form of controlled cell death than
necroptosis that does not release inflammatory signals into surrounding tissue.

Next, Dr.
Snyder activated RIPK3 protein in normal rather than cancerous cells and found
the same result: Injecting the necroptotic cells into tumors slowed their
growth and helped the mice live longer.

The finding,
Dr. Oberst said, showed that the dying cells were activating an immune response
in the tumor that did not depend on the immune system recognizing specific
markers on cancer cells.

“We
initially thought that the response would depend on tumor cells needing to die,
but the necroptotic cells are changing the tumor microenvironment to recruit
immune cells in the area,” Dr. Oberst said.

Further
tests showed that the inflammatory signals from necroptotic cells were
necessary to slow tumor growth. Additionally, the necroptotic cells appear to
recruit and activate phagocytes a type of immune cell that can engulf and
ingest unwanted cells. When cancer cells were labeled with fluorescent protein
before necroptotic cells were introduced, those fluorescent proteins ended up
in phagocytes, showing that the activated immune system had absorbed tumor
cells.

Stimulating
the Immune System

Rather than
injecting necroptotic cells into mouse tumors, the researchers found they could
instead deliver an activated form of the RIPK3 gene into tumor cells using an
engineered virus. The virus infected tumor cells and the activated RIPK3
triggered necroptosis, slowing tumor growth and improving how long the mice
lived.

Dr. Oberst
says he can see delivering RIPK3 into tumors as a therapeutic approach for
humans in the future. Regardless of the delivery method—using a virus, RNA
injection, or nanoparticles—generating an active form of the enzyme in tumors
is likely to help suppress their growth, Dr. Oberst said.

Finally, the
study showed that treating mice with an immune checkpoint inhibitor and
inducing necroptosis in the tumor at the same time had a synergistic effect.
That is, the combination killed cancer cells far more effectively than either
treatment approach alone, fully eliminating tumors in most of the mice and
preventing the same type of cancer cells from establishing a new tumor.

Next Steps

Douglas
Green, Ph.D., an immunologist at St. Jude Children’s Research Hospital, who was
not involved in the study, said that this approach of combining necroptosis
with immunotherapy has promise. “This work is at the cutting edge of research
on cell death and tumor immunotherapy.”

He added, “I
hope that we will see a direct extension of this work into practical, effective
cancer treatment. The strategy the authors outlined is readily adaptable for
human use.”

Dr. Salnikow
cautioned that it is difficult to predict how successfully and how soon this
approach could be implemented. But, he said, this work provides an important
advance in knowledge about anti-tumor immunity.

To help
develop their findings for possible clinical application, Dr. Oberst and his
team have begun working with industry partners. They are starting to extend
their findings to different mouse models that better mimic human cancer.

Because
cancer cells that arise in different tissues may produce different inflammatory
signals when they undergo necroptosis, the researchers are also working to
understand which cytokine signals released by necroptotic cells are most
important in activating an immune response in different tumors. Understanding
these differences, they believe, could help them engineer better approaches to
drive an immune response in different types of cancers.

Note (“Could A Form of Cell Death Enhance Cancer Immunotherapy? was originally published by the National Cancer Institute.”)