Lani
08-20-2007, 09:10 AM
tumors's ability to evade the immune system
and T reg cells have lots of FOXP3, the same gene recently found to be responsible for some, if not most, her2+ breast cancers, particularl ER+ ones. It is the X-linked gene I posted about this summer.
Here is an article and then an abstract:
Tumors use enzyme to recruit regulatory T-cells and suppress immune response [Medical College of Georgia]
One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.
It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.
"People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body," Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.
Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumor's draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. "The number doesn't change a lot, but their activation state changes hugely," says Dr. Munn, corresponding author.
Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.
The findings further define a tumor's survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.
"For the first time it creates a link between IDO, regulatory T cells and this novel pathway we don't know much about," says Dr. Munn. Interestingly it's a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.
Patients with breast cancer show early evidence of their tumors creating a safe environment for themselves within the lymph nodes by up-regulating cells expressing IDO"IDO appears to be a sort of linchpin; it's a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together," says Dr. Munn. "Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point."
Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.
^^^^^^^^^
ABSTRACT: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase [Journal of Clinical Investigation]
A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4+CD25+Foxp3+ Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls, and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were rown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs.
and T reg cells have lots of FOXP3, the same gene recently found to be responsible for some, if not most, her2+ breast cancers, particularl ER+ ones. It is the X-linked gene I posted about this summer.
Here is an article and then an abstract:
Tumors use enzyme to recruit regulatory T-cells and suppress immune response [Medical College of Georgia]
One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.
It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.
"People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body," Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.
Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumor's draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. "The number doesn't change a lot, but their activation state changes hugely," says Dr. Munn, corresponding author.
Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.
The findings further define a tumor's survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.
"For the first time it creates a link between IDO, regulatory T cells and this novel pathway we don't know much about," says Dr. Munn. Interestingly it's a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.
Patients with breast cancer show early evidence of their tumors creating a safe environment for themselves within the lymph nodes by up-regulating cells expressing IDO"IDO appears to be a sort of linchpin; it's a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together," says Dr. Munn. "Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point."
Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.
^^^^^^^^^
ABSTRACT: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase [Journal of Clinical Investigation]
A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4+CD25+Foxp3+ Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls, and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were rown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs.