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Impaired gp100-Specific CD8+ T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model  David G. Mairhofer,

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Presentation on theme: "Impaired gp100-Specific CD8+ T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model  David G. Mairhofer,"— Presentation transcript:

1 Impaired gp100-Specific CD8+ T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model  David G. Mairhofer, Daniela Ortner, Christoph H. Tripp, Sandra Schaffenrath, Viktor Fleming, Lukas Heger, Kerstin Komenda, Daniela Reider, Diana Dudziak, Suzie Chen, Jürgen C. Becker, Vincent Flacher, Patrizia Stoitzner  Journal of Investigative Dermatology  Volume 135, Issue 11, Pages (November 2015) DOI: /jid Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 The percentages of CD4+ T cells and Tregs are reduced in late-stage tumors of tg(Grm1)EPv mice. Cell suspensions from the skin and draining lymph nodes (LNs) of tumor-free, early-stage, and late-stage tumor tg(Grm1)EPv mice were analyzed by flow cytometry. (a) Percentages of CD45+ leukocytes are shown after pregating on viable cells (n=14 mice). For all further analyses, the percentages of cells were calculated based on CD45+ viable cells. (b and c) CD4+ and CD8+ T cells were analyzed in (b) the skin (n=8 mice) and (c) the draining LNs (n=15 mice). (d) Representative FACS plots for FoxP3+ CD25+ Tregs in the skin and draining LNs of tumor-free mice. (e) Summary graph for the percentages of FoxP3+ CD25+ Tregs in the skin and draining LNs (n≥8 mice). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Activated T cells are present in late-stage tumor mice and produce IFN-γ. Cell suspensions from draining lymph nodes (LNs) of tumor-free and late-stage tumor tg(Grm1)EPv mice were analyzed by flow cytometry. All analyses used a pregate on CD45+ viable cells. CD4+ and CD8+ T-cell subsets in draining LNs were analyzed for the following: (a) CD44hi CD62Llow T cells (n=11 mice) and (b) CD69+ activated T cells (n=8 mice). (c) IFN-γ-producing T cells were analyzed after restimulation of LN cells with antibodies against CD3 and CD28 for 48 h (n≥6 mice). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Endogenous glycoprotein 100 (gp100)-specific CD8+ T cells are present in late-stage tumors but are functionally impaired upon antigen-specific restimulation. Cell suspensions from the skin and draining lymph nodes (LNs) of tumor-free and late-stage tumor tg(Grm1)EPv mice were analyzed by flow cytometry for gp100-specific CD8+ T cells. All analyses used a pregate on CD45+ viable cells. (a) Representative FACS plots from a tumor-free tg(Grm1)EPv mouse for pentamer+ CD8+ T cells in the skin and draining LNs, pregate on viable CD8+ T cells. (b) Summary graph for pentamer+ CD8+ T cells in the skin and draining LNs (n≥9 mice). (c) Representative FACS plots from a tumor-free tg(Grm1)EPv mouse for IFN-γ production of CD8+ LN cells cultured without (untreated) or with gp100 peptide for 48 h. (d) Summary graph for gp100-responsive IFN-γ+ CD8+ cells calculated as following: ((mean of IFN-γ+ CD8+ cells restimulated with gp100 peptide)-(mean of IFN-γ+ CD8+ cells cultured without gp100 peptide))/(mean of unstimulated pentamer+ CD8+ cells), n≥4 mice. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 Myeloid-derived suppressor cells (MDSCs) accumulate in the skin and draining lymph nodes (LNs) of late-stage tumor mice. Cell suspensions of tumor-free, early-stage, and late-stage tumor tg(Grm1)EPv mice were analyzed by flow cytometry for the presence of CD11b+ Gr-1+ MDSCs in (a) the skin and (b) draining LNs (n=6 mice). MDSCs were further subdivided into CD11b+ Gr-1inter Ly-6Chigh monocytic MDSCs (moMDSCs) and CD11b+ Gr-1high Ly-6Clow granulocytic MDSCs (grMDSCs) in tumor-free and late-stage tumor tg(Grm1)EPv mice for (c) the skin and (d) the draining LNs (n=10 mice). All analyses used a pregate on CD45+ viable cells. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Myeloid-derived suppressor cells (MDSCs) in the tumor are potent suppressors of T-cell activity. Sorted MDSC subsets from ear and tail skin of late-stage tumor tg(Grm1)EPv mice were used to suppress CD8+ T–cell proliferation. (a) glycoprotein 100 (gp100)-specific pmel-1 CD8+ T cells (2 × 104) were purified, CFSE-labeled (0.4 μM), and cultured for 3 days together with gp100 peptide–pulsed bone marrow–derived dendritic cells (BMDCs; 1 × 102). Sorted grMDSCs (1 × 104) or moMDSCs (1 × 104) were added to cultures, and proliferation of T cells was measured (n=3 experiments). (b-d) Quantitative PCR analysis of sorted granulocytic MDSC (grMDSCs) and monocytic MDSC (moMDSCs) from six late-stage tg(Grm1)EPv mice in comparison with CD45- tumor cells and CD45+ CD11b- leukocytes was performed for (b) Arginase-1, (c) inducible nitric oxide synthase (iNOS), and (d) transforming growth factor-β (TGF-β). (e–h) Representative histograms from skin MDSCs and summary graphs of the percentages of positive MDSCs in the skin and draining LNs from late-stage tg(Grm1)EPv mice are shown for (e and f) Arginase-1 and (g and h) iNOS, (n=6 mice). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

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