Though a variety of immunotherapy-based strategies
are being used against cancer, they are often
hindered by the inability of the immune response to
enter the immunosuppressive tumor microenvironment
and to effectively mount a response to cancer cells.
Now, scientists from the RIKEN Center for
Integrative Medical Sciences have developed a new
vaccine that involves injecting cells that have been
modified so that they can stimulate both an innate
immune response and the more specific adaptive
response, which allows the body to keep memories and
attack new tumor cells as they form. In the study
published in Cancer Research, they found that the
vaccine made it possible for killer
CD8+T-cells—important players in the immune response
against cancer—to enter the tumor microenvironment
and target cancerous cells.
According to Shin-ichiro Fujii, leader of the
Laboratory for Immunotherapy, who led the study,
“Cancer cells have different sensitivities to the
innate or adaptive response, so it important to
target both in order to eradicate it. We have
developed a special type of modified cell, called
aAVC, which we found can do this.”
The aAVC cells are not taken from the subject’s own
body but are foreign cells. The cells are modified
by adding a natural killer t-cell ligand, which
permits them to stimulate natural killer T-cells,
along with an antigen associated with a cancer. The
group found that when these cells are activated,
they in turn promote the maturation of dendritic
cells, which act as coordinators of the innate and
acquired response. Dendritic cells are key because
they allow the activation of immune memory, where
the body remembers and responds to a threat even
years later.
To find whether it worked in actual bodies, they
conducted experiments in mice with a virulent form
of melanoma that also expresses a model antigen
called OVA. Tests in mice showed, moreover, that
aggressive tumors could be shrunken by vaccinating
the animals with aAVC cells that were programmed to
display OVA antigen. Following the treatment, the
tumors in the treated animals were smaller and
necrotic in the interior—a sign that the tumor was
being attacked by the killer CD8+T-cells.
Fujii continues, “We were interesting in finding a
mechanism, and were able to understand that the aAVC
treatment led to the development of blood vessels in
the tumors that expressed a pair of important
adhesion molecules, ICAM-1 and VCAM-1, that are not
normally expressed in tumors. This allowed the
killer CD8+T cells to penetrate into the tumor.”
They also found that in animals that had undergone
the treatment, cancer cells injected even a year
later were eliminated. “This indicates,” says Fujii,
“that we have successfully created an immune memory
that remembers the tumor and attacks it even later.”
Looking to the future, Fujii says, “Our therapy with
aAVC is promising because typical immunotherapies
have to be tailor-made with the patient’s own cells.
In our case we use foreign cells, so they can be
made with a stable quality. Because we found that
our treatment can lead to the maturation of
dendritic cells, immunotherapy can move to local
treatment to more systemic treatment based on immune
memory.”
For more information
Cancer Research
Kanako Shimizu, Satoru Yamasaki, Jun Shinga, Yusuke
Sato, Takashi Watanabe, Osamu Ohara, Kiyotaka
Kuzushima, Hideo Yagita, Yoshiko Komuro, Miki
Asakura, and Shin-ichiro Fujii;
Systemic DC activation modulates the tumor
microenvironment and shapes the long-lived
tumor-specific memory mediated by CD8+ T cells
doi: 10.1158/0008-5472.CAN-15-3219
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