|Prostate Tumors Can Change the Function
of Immune Cells in Mice
Researchers have discovered that prostate tumors in mice can cause
immune cells known as CD8+ T cells to change their function
from cells that have antitumor activity to cells that suppress
immune responses. This finding, by researchers at the National
Cancer Institute (NCI), part of the National Institutes of Health,
has important implications for the design of immune-based therapies
for cancer. The new study, available online, appears in the Oct.
15, 2009, issue of the Journal of Immunology.
"The conversion of CD8+ T cells into suppressor cells
may be one of the mechanisms by which tumors restrict the immune
systemís ability to control tumor growth," said Arthur A. Hurwitz,
Ph.D., head of the Tumor Immunity and Tolerance Group at NCIís
Center for Cancer Research. "Studying this process in mice may
help explain why some cancer patients have an initial response
from their immune-based therapy, but this response fails with time."
In mice and humans, when the immune system encounters a pathogen
or other foreign invader, it responds by mounting an immune response.
Part of this response involves the recruitment and activation of
CD8+ T cells, which are also called cytotoxic T cells
or killer T cells, to help destroy the invader. CD8+ T
cells also play a role in immune responses against tumor cells.
Other T cells, known as CD4+ T regulatory cells, work
to suppress CD8+ T cell activity. Immune suppression
by these regulatory T cells helps prevent the body from attacking
its own cells. A high level of CD4+ T regulatory cells
is also associated with poor prognosis of some cancers. Moreover,
research in mice has shown that blocking the immune suppressive
activity of these regulatory T cells enhances the bodyís immunity
against tumors, causing tumor growth to slow and improving the
antitumor immune responses elicited by cancer vaccines.
Recent evidence in mice has suggested that CD8+ T cells
can develop suppressive activities similar to those of CD4+ T
regulatory cells. In addition, CD8+ suppressor cells
have been found in cancer patients. The presence of these suppressor
cells could explain earlier findings by Hurwitzís team that prostate
tumor-specific CD8+ T cells injected into prostate tumor-bearing
mice migrate to the tumors but then become unresponsive, or tolerized,
to the tumor cells. It remained unclear, however, whether the suppressive
CD8+ T cells have suppressor activity before they reach
the tumor or whether they are converted into suppressor cells by
In the new research, Hurwitzís team found that CD8+ T
cells acquire immune suppressive functions after they enter the
mouse tumor microenvironment, which encompasses nearby noncancerous
cells and immune cells in addition to tumor cells. The researchers
found that tumor-specific CD8+ T cells isolated from
the tumors were able to suppress the proliferative capacity of
nonspecific T cells, whereas tumor-specific CD8+ T cells
isolated from lymph nodes of the mice were unable to do so.
This anti-proliferative activity appeared to be caused, in part,
by substances secreted by the CD8+ T cells after they
had been converted to suppressor cells. One of these substances,
TGF-beta, is a protein that controls cell proliferation and differentiation
and plays a role in cancer and other diseases. TGF-beta is thought
to be involved in the immune-suppressive activity of CD4+ T-regulatory
Next, the team investigated whether the conversion of tumor-specific
CD8+ T cells to suppressor cells could be prevented.
To do this, they administered tumor-specific CD4+ and
CD8+ T cells to prostate tumor-bearing mice. Some CD4+ T
cells act as helper cells and enhance the activity of other immune
cells, including CD8+ T cells. The researchers found
that, under these conditions, CD8+ T cells isolated
from the prostate tumors no longer suppressed the proliferation
of other T cells. Moreover, these cells produced less TGF-beta
than cells that were not exposed to CD4+ T cells.
The researchers propose that activated CD4+ T cells
that enter tumors may secrete factors that support the CD8+ T
cell antitumor functions, or may help other immune cells located
in the tumor block the processes by which CD8+ T cells
acquire their suppressive activity.
Future work by this team will focus on defining the mechanisms
by which tumor-specific CD8+ T cells gain their suppressive
functions upon entering the mouse tumor microenvironment. "It is
important to understand how these cells become suppressive and
how they mediate suppression to find approaches to block these
processes," said Hurwitz. "This will enhance our ability to generate
more effective antitumor T cell responses in mice, which then might
be translated to human."
For more information on Dr. Hurwitzís research, please go to http://ccr.nci.nih.gov/staff/staff.asp?profileid=7740.
NCI leads the National Cancer Program and the NIH effort to dramatically
reduce the burden of cancer and improve the lives of cancer patients
and their families, through research into prevention and cancer
biology, the development of new interventions, and the training
and mentoring of new researchers. For more information about cancer,
please visit the NCI Web site at http://www.cancer.gov or call
NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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Shafer-Weaver, KA, Anderson, MJ, Stagliano K, Malyguine, A, Greenberg, NM, and Hurwitz AA. Cutting Edge: Tumor-Specific CD8+ T Cells Infiltrating Prostatic Tumors Are Induced to Become Suppressor Cells. J Immunol. Oct. 15, 2009. Vol. 183, No. 8.