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How Treg are induced in cancer is poorly understood. We reported previously that Treg are significantly elevated in the peripheral blood of patients with pancreas cancer and that in a murine pancreas cancer model induction of Treg appears to be TGF-Beta dependent.
Here we provide additional evidence that Treg are increased locally within the tumor microenvironment by a mechanism that appears dependent on TGF-Beta Receptor expression and the presence of tumor derived TGF-Beta. The murine pancreas cancer cell line Pan02 produces high levels of TGF-Beta both in vitro and in vivo.
However, thymus-derived natural Treg (tTreg or nTreg) expansion or recruitment could also contribute to the lymphocyte response after lung injury because adoptive transfer of 1 × 10 6 splenic nTregs mediates resolution in lymphocyte-deficient mice (3, 5). In summary, Treg are a critical component of self-tolerance and many forms of induced tolerance to exogenous antigens, including tolerance to coagulation factors in gene- or protein-based therapies. Moreover, Treg suppress B and T cell responses to coagulation factors and cells expressing these therapeutic proteins. The development of Treg cells from transferred Nfkbid +/+ or Nfkbid −/− T cells, was analyzed by flow cytometry. Representative pseudocolor dot-plots of CD4 + Foxp3 + Treg cells from the lamina propria pregated on CD4 + T cells and statistical summary are shown.
In contrast, the esophageal murine cancer cell line, Eso2, does not. Collectively these observations further support the role of TGF-Beta in the induction of Treg in pancreas adenocarcinoma. Like many tumors, pancreas cancer is weakly immunogenic and is associated with a poor anti-tumor immune response 1 ; 2.
This in part is due to the chronically immunosuppressed state that pancreas cancer patients exist. Their serum level of the immunosuppressive cytokine, TGF-Beta 3 ; 4can as much as 4.
Furthermore, pancreas cancer patients have reduced number and function of circulating dendritic cells 6 ; 7. What is interesting is that post-adjuvant treatment dendritic cell numbers and function recover while there also is a reciprocal drop in systemic TGF-Beta levels.
Taken together it suggests that logically this state of immunosuppression is detrimental to the host. Adding to this there is now evidence that pancreas cancer patients have elevated numbers of the suppressor T cell, Treg 8 - As well, elevated numbers of Treg in ovarian cancer is associated with less favorable outcomes Yet little is known for how modern medical therapeutics can be used to reverse this immunosuppressive state.
To do so, it would be necessary to better understand the mechanisms by which tumors suppress anti-tumor effector responses.
The elevation of Treg in cancer suggests one mechanism by which tumors induce immunosuppression. They can be subdivided into two main categories: Where nTreg and iTreg differ is in their origin, antigen specificity, and mechanism of suppression Natural Treg nTreg are thymus derived, constitutively express CD25, and their mechanism of suppression is cell contact dependent Natural and inducible Treg cells can be protective to the host during states of autoimmunity, infection, or transplant rejection.
In malignancy, however, Treg play a critical role in progression of tumor growth and suppression of antitumor immune responses 11 ; 21 - A few preliminary reports suggest that iTreg play a more significant role in suppressing anti-tumor immunity than nTreg 25 - Furthermore human trials that non-selectively neutralized both nTreg and iTreg function using CD25 directed immunotoxins resulted in diseases of autoimmunity and only transient partially reduced populations of Treg 28 - The induction of autoimmunity in these hosts likely results from the unintended neutralization of nTreg function as well as the tumor iTreg.
What these findings at least suggest is that selective depletion of certain Treg subtypes may be a more efficient and possibly effective way of overcoming Treg suppression in cancer patients.
These techniques, however, cannot be developed until we better understand how tumors induce Treg. In this study, we demonstrate in a murine pancreas cancer model that a high prevalence of tumor induced Treg is associated with elevated systemic levels of TGF-Beta.
These tumor-derived Treg have in vitro Treg suppressor function identical to that of nTreg. Collectively these findings suggest that murine pancreas tumors induce Treg prevalence through a mechanism that appears to be TGF-Beta dependent.To elucidate whether IκB NS is crucial for the function and maintenance of mature Treg cells, we examined the expression of Treg cell signature proteins CD25 (IL-2Rα), GITR, Foxp3, CD (IL-2Rβ), and CTLA-4 in Treg cells from Nfkbid-deficient and WT mice.
However, thymus-derived natural Treg (tTreg or nTreg) expansion or recruitment could also contribute to the lymphocyte response after lung injury because adoptive transfer of 1 × 10 6 splenic nTregs mediates resolution in lymphocyte-deficient mice (3, 5).
Affiliation Diabetes Center, University of California San Francisco, San Francisco, California, United States of America The use of viral gene transfer in Treg therapy settings confers the ability to address several important safety concerns.
Gao W, Friedman D, Usheva A, et al. () Adenosine generation catalyzed by CD39 and CD The expression of CD25 by Treg cells is likely a corollary of continuous stimulation of Treg cells by self-antigens (Maçon-Lemaître and Triebel, Maçon-Lemaître L, Triebel F. (). The negative regulatory function of the lymphocyte-activation Gene-3 Co-Receptor (CD) on Human T Cells.
In summary, Treg are a critical component of self-tolerance and many forms of induced tolerance to exogenous antigens, including tolerance to coagulation factors in gene- or protein-based therapies.
Moreover, Treg suppress B and T cell responses to coagulation factors and cells expressing these therapeutic proteins. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development.
The dual role of Treg in cancer and underpinnings of Treg diversity are not well understood.