The Experts below are selected from a list of 69 Experts worldwide ranked by ideXlab platform
Anna Casati - One of the best experts on this subject based on the ideXlab platform.
-
Hierarchy of immunosuppressive strength among Myeloid-Derived Suppressor Cell subsets is determined by GM-CSF
European Journal of Immunology, 2010Co-Authors: Luigi Dolcetti, Elisa Peranzoni, Stefano Ugel, Ilaria Marigo, Audry Fernandez Gomez, Circe Mesa, Markus Geilich, Gregor Winkels, Elisabetta Traggiai, Anna CasatiAbstract:CD11b+/Gr-1+ Myeloid-Derived Suppressor Cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8+ T-Cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b+/Gr-1high, CD11b+/Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int Cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-Cell activation, while CD11b+/Gr-1high Cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b+/Gr-1int but not CD11b+/Gr-1high Cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low Cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b+/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high Cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low Cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.
James P Allison - One of the best experts on this subject based on the ideXlab platform.
-
pd 1 and ctla 4 combination blockade expands infiltrating t Cells and reduces regulatory t and myeloid Cells within b16 melanoma tumors
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Michael A Curran, Welby Montalvo, Hideo Yagita, James P AllisonAbstract:Vaccination with irradiated B16 melanoma Cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-Cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-Cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding αPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-Cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-Cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of Cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-Myeloid-Derived Suppressor Cell ratios within B16 melanomas. IFN-γ production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-γ/TNF-α double-producing CD8+ T Cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T Cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
Luigi Dolcetti - One of the best experts on this subject based on the ideXlab platform.
-
Hierarchy of immunosuppressive strength among Myeloid-Derived Suppressor Cell subsets is determined by GM-CSF
European Journal of Immunology, 2010Co-Authors: Luigi Dolcetti, Elisa Peranzoni, Stefano Ugel, Ilaria Marigo, Audry Fernandez Gomez, Circe Mesa, Markus Geilich, Gregor Winkels, Elisabetta Traggiai, Anna CasatiAbstract:CD11b+/Gr-1+ Myeloid-Derived Suppressor Cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8+ T-Cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b+/Gr-1high, CD11b+/Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int Cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-Cell activation, while CD11b+/Gr-1high Cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b+/Gr-1int but not CD11b+/Gr-1high Cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low Cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b+/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high Cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low Cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.
Marcela C Diazmontero - One of the best experts on this subject based on the ideXlab platform.
-
myeloid derived Suppressor Cell subset accumulation in renal Cell carcinoma parenchyma is associated with intratumoral expression of il1β il8 cxcl5 and mip 1α
Clinical Cancer Research, 2017Co-Authors: Yana G Najjar, Patricia Rayman, Paul G Pavicic, Brian I Rini, Charles S Tannenbaum, Jennifer S Ko, Samuel Haywood, Peter A Cohen, Thomas A Hamilton, Marcela C DiazmonteroAbstract:Purpose: Little is known about the association between Myeloid-Derived Suppressor Cell (MDSC) subsets and various chemokines in patients with renal Cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-Cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-Cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 1–10. ©2016 AACR.
Michael A Curran - One of the best experts on this subject based on the ideXlab platform.
-
pd 1 and ctla 4 combination blockade expands infiltrating t Cells and reduces regulatory t and myeloid Cells within b16 melanoma tumors
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Michael A Curran, Welby Montalvo, Hideo Yagita, James P AllisonAbstract:Vaccination with irradiated B16 melanoma Cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-Cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-Cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding αPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-Cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-Cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of Cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-Myeloid-Derived Suppressor Cell ratios within B16 melanomas. IFN-γ production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-γ/TNF-α double-producing CD8+ T Cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T Cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
