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Duke Researchers Discover Protein that can Alert Immune System to Fight Cancer

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Duke Health News 919-660-1306

DURHAM, N.C. -- Researchers at Duke University Medical
Center have discovered that an ancient protein can perform a
decidedly modern function: stimulating the immune system to
fight tumors.

The protein, called calreticulin, belongs to a family of
proteins called chaperones that help fold other proteins into
their globular working shapes after they are synthesized as
string-like molecules inside the cell. These evolutionarily
ancient proteins are found in all mammalian cells and have
relatives in organisms as simple as bacteria and yeast.

But calreticulin can perform another vital function, the
researchers discovered. Through experiments in mice, scientists
found it can act as an informant to the immune system,
stimulating it to destroy skin and thymus cancers.

The two disparate functions appeared to be difficult to
reconcile. But now Duke cell biologist Christopher Nicchitta
has begun to resolve the mystery, demonstrating that at least
two chaperone proteins appear to have evolved a dual function:
assisting protein folding inside the cell and alerting the
immune system if they are released from the cell, as happens
when tissue is under assault from inflammation, wounding or
autoimmune attack.

The discovery is described and explained in two papers in
the June 1 issue of the Journal of Immunology and the
July 1 issue of the Journal of Cell
Science.

"Calreticulin and its relatives are complex molecules that
appear to have evolved a second function," Nicchitta said.
"Since they normally are found only inside the cell, when they
are released they can act as a danger signal to the immune
system, which responds by trying to eliminate the insult at the
precise location in the body signaled by these proteins."

The work, which was supported by the National Institutes of
Health, is part of Duke's Center for Genetic and Cellular
Therapies continuing effort to coax the body's own immune
system to fight cancer. If further research proves the proteins
act the same way in humans, it may help scientists tailor
specific cancer therapies, said Nicchitta.

So far, the scientists' experiments reveal that calreticulin
and a related protein called GRP94 both can alert the immune
system by informing it about where in the body an insult has
occurred. The proteins act as informants by carrying small
pieces of cellular proteins called peptides as a type of
calling card, with an address describing where in the body the
injury is; for example, the skin or the thymus.

"The peptides appear to act as a fingerprint of the cell,"
Nicchitta said. "They tell the immune system where to marshal
its forces. We are now using that property of these chaperone
proteins to educate the immune system to fight cancer."

These molecular calling cards act as immune stimulating
substances called antigens and are recognized by specialized
immune system cells, either macrophages or dendritic cells.
When these immune cells come into contact with calreticulin or
GRP94, they appear to swallow the protein, release the peptides
and display them on their cell surface. This display of a
foreign peptide can trigger a strong response from immune
system fighters known as killer T cells.

The Duke researchers showed that when they injected mice
with dendritic cells that had been mixed with calreticulin or
GRP94 purified from melanoma (skin cancer) or thymoma (thymus
tumors), the animals responded by generating large numbers of
killer T cells directed at the specific tumor type from which
it had come.

"The immune response mediated by calreticulin is
impressive," said Dr. Eli Gilboa, research director of Duke's
Center for Genetic and Cellular Therapies. "This result shows
the promise of this class of proteins to elicit a targeted
cytotoxic T lymphocyte (killer T cell) response to tumor
tissue."

Tumor cells have evolved ways of effectively hiding from
patrolling dendritic cells, making cancer virtually invisible
to the immune system, which can only mount a very weak response
at best. The Duke researchers, led by Gilboa, have devised a
way to engineer dendritic cells and grow them in the lab, and
they have been testing various methods to prompt the cells to
recognize cancerous tumors, thus targeting them for
destruction.

Upon hearing that researchers at other institutions had
successfully used GRP94 to mount an immune response, Gilboa and
his colleagues launched a collaboration with Nicchitta, who had
been studying the chaperone proteins for many years. Before
long, the researchers had discovered that calreticulin is even
better than GRP94 in stimulating the immune system. That work
is the subject of the June 1 Journal of Immunology paper.

The finding prompted Nicchitta and his colleagues James
Wassenberg and Cameron Dezfulian to examine just how a
protein-folding chaperone might stimulate the immune system.
Their findings are detailed in the July 1 issue of the Journal
of Cell Science.

"To our surprise, we found that macrophages have a specific
receptor on their cell surface that recognizes GRP94 and
internalizes it," said Nicchitta. "The question is why would
macrophages have a receptor on the exterior of the cell for a
protein that is normally found only inside cells?"

Nicchitta speculates that the researchers have come across a
previously unknown role for chaperone proteins.

The scientists are now trying to determine the pathway that
antigen-presenting cells like macrophages and dendritic cells
use to convert the molecular flags carried by chaperone
proteins into a specific immune response.

Meanwhile, Gilboa and his colleague immunologist Smita Nair
are beginning to explore the use of chaperone proteins as a
basis for a new type of cancer vaccine.

"We are enthusiastic about the response we have seen to our
vaccine in animals," Gilboa said. However, he cautions that
such a vaccine is still far from ready for trials in
people.

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