TY - JOUR
T1 - IL-10 immunomodulation of myeloid cells regulates a murine model of ovarian cancer
AU - Hart, Kevin M.
AU - Byrne, Katelyn T.
AU - Molloy, Michael J.
AU - Usherwood, Edward M.
AU - Berwin, Brent
PY - 2011
Y1 - 2011
N2 - Elevated levels of IL-10 in the microenvironment of human ovarian cancer and murine models of ovarian cancer are well established and correlate with poor clinical prognosis. However, amongst a myriad of immunosuppressive factors, the actual contribution of IL-10 to the ovarian tumor microenvironment, the mechanisms by which it acts, and its possible functional redundancy are unknown. We previously demonstrated that elimination of the myeloid-derived suppressor cell (MDSC) compartment within the ovarian tumor ascites inhibited tumor progression and, intriguingly, significantly decreased local IL-10 levels. Here we identify a novel pathway in which the tumor-infiltrating MDSC are the predominant producers of IL-10 and, importantly, require it to develop their immunosuppressive function in vivo. Importantly, we demonstrate that the role of IL-10 is critical, and not redundant with other immunosuppressive molecules, to in vivo tumor progression: blockade of the IL-10 signaling network results in alleviation of MDSC-mediated immunosuppression, altered T cell phenotype and activity, and improved survival. These studies define IL-10 as a fundamental modulator of both MDSC andT cells within the ovarian tumor microenvironment. Importantly, IL-10 signaling is shown to be necessary to the development and maintenance of a permissive tumor microenvironment and represents a viable target for anti-tumor strategies.
AB - Elevated levels of IL-10 in the microenvironment of human ovarian cancer and murine models of ovarian cancer are well established and correlate with poor clinical prognosis. However, amongst a myriad of immunosuppressive factors, the actual contribution of IL-10 to the ovarian tumor microenvironment, the mechanisms by which it acts, and its possible functional redundancy are unknown. We previously demonstrated that elimination of the myeloid-derived suppressor cell (MDSC) compartment within the ovarian tumor ascites inhibited tumor progression and, intriguingly, significantly decreased local IL-10 levels. Here we identify a novel pathway in which the tumor-infiltrating MDSC are the predominant producers of IL-10 and, importantly, require it to develop their immunosuppressive function in vivo. Importantly, we demonstrate that the role of IL-10 is critical, and not redundant with other immunosuppressive molecules, to in vivo tumor progression: blockade of the IL-10 signaling network results in alleviation of MDSC-mediated immunosuppression, altered T cell phenotype and activity, and improved survival. These studies define IL-10 as a fundamental modulator of both MDSC andT cells within the ovarian tumor microenvironment. Importantly, IL-10 signaling is shown to be necessary to the development and maintenance of a permissive tumor microenvironment and represents a viable target for anti-tumor strategies.
KW - IL-10
KW - MDSC
KW - Ovarian cancer
KW - T cell
UR - http://www.scopus.com/inward/record.url?scp=84869221347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869221347&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2011.00029
DO - 10.3389/fimmu.2011.00029
M3 - Article
AN - SCOPUS:84869221347
SN - 1664-3224
VL - 2
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUL
M1 - Article 29
ER -