PROSTATE TUMORS CAN CHANGE THE FUNCTION OF IMMUNE CELLS IN MICE

From an NIH press release:

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 system's ability to control tumor growth," said Arthur A. Hurwitz, Ph.D., head of the Tumor Immunity and Tolerance Group at NCI's 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 body's 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 Hurwitz's 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 the tumor.

In the new research, Hurwitz's 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 cells.

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. Hurwitz's research, please go to .

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 or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .

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REFERENCE:
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.


U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Cancer Institute (NCI)
For Immediate Release: Wednesday, October 7, 2009

CONTACT: NCI Office of Media Relations, 301-496-6641,

MicroRNAS IN BLOOD MAY BE BIOMARKERS OF PANCREATIC CANCER

We desperately need this new test for pancreatic cancer and we need a cure ASAP. - BRH.

MicroRNAS IN BLOOD MAY BE BIOMARKERS OF PANCREATIC CANCER

Small molecules known as microRNAs, which can be detected in blood samples, have the potential to help identify patients with pancreatic cancer, a study finds. The study, by researchers at The University of Texas M.D. Anderson Cancer Center in Houston, was supported by the Early Detection Research Network (EDRN) of the National Cancer Institute (NCI), part of the National Institutes of Health. The paper appeared online Sept. 1, 2009, in Cancer Prevention Research.

Pancreatic cancer is a highly fatal disease that is difficult to detect at early stages. In most patients, symptoms do not appear until the cancer is locally advanced or has spread to other parts of the body. The absence of symptoms in early-stage disease and the current lack of effective, minimally invasive screening and diagnostic techniques limit the available treatment options. Both contribute to the high mortality rate observed for patients with pancreatic cancer.

"The development of a minimally invasive test for the early detection and diagnosis of pancreatic cancer is greatly needed," said Sudhir Srivastava, Ph.D., chief of the Cancer Biomarkers Research Group in NCI's Division of Cancer Prevention. "An important step is to identify biomarkers for pancreatic cancer, such as microRNAs, circulating in the bloodstream that can be used to distinguish individuals with pancreatic cancer from individuals without the disease."

MicroRNAs, or miRNAs, are short strands of RNA. The miRNAs regulate gene expression by controlling the translation of a specific type of RNA called messenger RNA which relays the genetic instructions for making proteins. Previous research has indicated that miRNAs play important roles in regulating normal cell proliferation and in cancer. Altered patterns of miRNA expression have been seen in pancreatic cancer as well as many other cancers. In addition, it has recently been reported that tumor-derived miRNAs can be detected in blood and that these molecules are stable in stored samples. Thus, miRNAs circulating in the blood may have the potential to serve as novel biomarkers for the detection and diagnosis of pancreatic cancer.

To evaluate the feasibility of using miRNAs in the blood as biomarkers for pancreatic cancer, the researchers selected a set of four miRNAs that have been associated with pancreatic cancer -- miR-21, miR-210, miR-155, and miR-196a. Among these, miR-155 has been identified as a candidate biomarker for early pancreatic cancer, and expression of miR196a has been shown to increase during disease progression. Levels of all four miRNAs were assessed in blood samples from 28 pancreatic cancer patients and 19 healthy volunteers. The study population consisted of patients with pathologically confirmed pancreatic cancer and healthy disease free individuals recruited at the M.D. Anderson Cancer Center between 2002 and 2008. The team found that sensitivity -- or ability to accurately detect pancreatic cancer -- using the panel of four miRNAs was 64 percent. The panel also showed an 89 percent specificity, which indicates the proportion of study participants who did not have pancreatic cancer and were correctly identified as being disease free.

"Our results demonstrate proof of principle in developing a blood test based on miRNA signatures for pancreatic cancer," said senior author Subrata Sen, Ph.D., of M.D. Anderson's Department of Molecular Pathology. "More work is needed to evaluate this strategy in different grades and stages of the disease. We are in the process of initiating such studies in collaboration with members of EDRN." For example, the researchers will test the ability of the miRNAs to detect pancreatic cancer in separate patient populations.

Pancreatic cancer, the fourth most common cause of cancer death in the United States, has a poor survival rate compared with that of other types of cancer. Less than five percent of the patients with pancreatic cancer survive five years past diagnosis.

For more information about the Department of Molecular Pathology at M.D. Anderson, please go to .

For more information on NCI's EDRN, please go to: .

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 or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .

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This NIH News Release is available online at:
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U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Cancer Institute (NCI)
Embargoed for Release: Tuesday, September 1, 2009, 1 p.m., EDT

CONTACT: NCI Office of Media Relations, 301-496-6641, ncipressofficers@mail.nih.gov>