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The E3 Ubiquitin Ligase Asb2α in T Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer

Camille A. Spinner, Isabelle Lamsoul, Arnaud Métais, Chanaëlle Febrissy, Christel Moog-Lutz and Pierre G. Lutz
Camille A. Spinner
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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Isabelle Lamsoul
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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  • ORCID record for Isabelle Lamsoul
  • For correspondence: Pierre.Lutz@ipbs.fr Isabelle.Lamsoul@ipbs.fr
Arnaud Métais
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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Chanaëlle Febrissy
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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Christel Moog-Lutz
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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Pierre G. Lutz
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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  • For correspondence: Pierre.Lutz@ipbs.fr Isabelle.Lamsoul@ipbs.fr
DOI: 10.1158/2326-6066.CIR-18-0562 Published August 2019
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    Figure 1

    Asb2α expression was positively regulated by Gata3 in Th2 cells. A, Relative expression of Asb2α mRNA in naïve CD4+ T cells, Th1, Th2, Treg, and Th17 cells of wild-type mice assessed by qRT-PCR. The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM. B, Asb2 expression detected using Affymetrix gene chip in naïve CD4+ T cells, Th1, Th2, Treg, and Th17 cells are plotted from the GSE14308 (29). C, Total island tag counts of lineage-specific H3K4me3 and H3K27me3 in the Asb2 locus in naïve CD4+ T cells, Th1, Th2, Treg, and Th17 cells are plotted from the GSE14308 (29). D, Genome browser image showing Gata3 binding pattern at the genomic region containing Prima1, Fam181a, Asb2, Otub2, Ddx24, and Ifi27 genes in Th2 cells. Genome browser images showing the patterns of Gata3 and Fli1 binding, as well as H3K4me1, H3K4me2, H3K4me3, and H3K27me3 modifications at the Asb2 gene in Th2 cells. Peaks identified with P ≤ 10−13 are plotted from the GSE20898 (30) using the Integrative Genome Viewer. E, Sequences of the Gata3 and Ets binding sites in the Asb2 locus are aligned to their respective top motifs in Th2 cells (30). **, P < 0.01; ***, P < 0.001.

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    Figure 2.

    ASB2 expression in human colorectal cancer biopsies correlated with shorter relapse-free survival. Microarray expression data (GSE39582) from human colorectal cancer biopsies containing tumor cells, stroma, and infiltrate (28) were analyzed for expression of ASB2, CD45/PTPRC, c-MAF, GATA3, and IRF4. A, Scatter plots showing correlation data for ASB2 and CD45/PTPRC, ASB2 and GATA3, ASB2 and c-MAF, and ASB2 and IRF4 transcripts in human colorectal cancer biopsies (n = 250). Linear regression-fit curves are shown as red lines. Correlations between nonparametric variables were evaluated using Spearman rank correlation test (r). B, ASB2 expression in the C1 (n = 55), C2 (n = 55), C3 (n = 27), C4 (n = 26), C5 (n = 61), and C6 (n = 26) subtypes of colorectal cancers as defined by Marisa and colleagues (28). Boxplots (with lower quartile, median, and upper quartile, Tukey whiskers) are shown. C, Kaplan–Meier curves showing relapse-free survival rates in patients with high (ASB2high; n = 8), intermediate (ASB2int; n = 138), and low (ASB2low; n = 104) ASB2 expression. Relapse-free survival curves were assessed for statistically significant differences using the Log-rank (Mantel–Cox) test. D, Percentages of the C1–C6 subtypes in the ASB2high, ASB2int, and ASB2low groups. **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

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    Figure 3.

    Deletion of Asb2 attenuated colitis-associated tumor formation and development. Control (ctrl) and cKO mice were injected with AOM, subsequently treated with the indicated cycles of DSS, and analyzed 69 (B–H) or 43 (I–K) days after AOM injection. A, Schematic representation of AOM/DSS-induced colorectal cancer treatment. B, Representative image of colons. Scale bar = 0.5 cm. C, Representative colon sections stained with alcian blue and nuclear fast red. Scale bar = 200 μm. D, Expression of Asb2α transcripts in spleen cells. E, Expression of Asb2α transcripts in sorted CD45+ and CD45− cells isolated from colonic tissues of AOM/DSS-treated mice. F, Colon lengths after treatment. G, Tumor loads in the colon. H, Enumeration of total tumor burden and of tumors following classification according to their size. I, Colon lengths after treatment. J, Tumor loads in the colon. K, Enumeration of total tumor burden and of tumors following classification according to their size. L, Schematic representation of AOM/DSS-induced colorectal cancer treatment after bone marrow reconstitution of C57BL/6 CD45.1–irradiated mice with bone marrow cells from Mx1-Cre;Asb2fl/fl or Mx1-Cre mice. Representative colon sections stained with alcian blue and nuclear fast red and tumor loads are shown. Scale bar = 200 μm. The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM (sample size, Ctrl = 9 and cKO = 7 for D; Ctrl = 4 and cKO = 4 for E; Ctrl = 25 and cKO = 20 for F–H; Ctrl = 10 and cKO = 8 for I–K; and Mx1-Cre = 5 and Mx1-Cre;Asb2fl/fl = 4 for L). *, P < 0.05; **, P < 0.01.

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    Figure 4.

    Emergency myelopoiesis in the bone marrow and the spleen of tumor-bearing mice. Control (ctrl) and cKO mice were left untreated (−) or treated with AOM and DSS (A/D). Cells were isolated from peripheral blood (A), bone marrow (B), and colon (C) 43 (d43) or 69 days (d69) after AOM injection and analyzed by flow cytometry. A, Peripheral blood parameters including numbers of lymphocytes, monocytes, granulocytes, platelets, and red blood cells. B, Cellularity of the bone marrow and numbers of the indicated bone marrow populations (see Materials and Methods or see below for definitions). C, Cellularity of the spleen and numbers of the indicated spleen populations (see Materials and Methods or see below for definitions). The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM. In B and C, monocytes/macrophages are CD45+F4/80+CD11b+, dendritic cells are CD45+CD11c+, B cells are CD45+CD19+CD45R+, and T cells are CD45+CD3+. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

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    Figure 5.

    Decreased Th2/Treg and increased Th1/Th17/CTL responses in cKO mice trigger antitumor immunity to inhibit colitis-associated tumorigenesis. Control (ctrl) and cKO mice were treated with AOM and DSS and the cells isolated from colons 43 (d43) or 69 days (d69) after AOM injection were analyzed by flow cytometry and qRT-PCR. A, Data represents the numbers of CD45+CD4+ cells. B, Data represents the numbers of CD45+CD4+IL4+ and CD45+CD4+IL13+ cells. C, Data represents the numbers of IL10+ Treg cells (CD45+CD4+FoxP3+IL10+). D, Representative flow cytometry plots for CD4 versus IFNγ within a CD45+CD4+ gate and numbers of CD45+CD4+IFNγ+ cells. Values inside the plots represent the percentages from the CD45+CD4+ gate. E, Data represents the numbers of Th17 cells (CD45+CD4+IL17A+). F, Data represents the numbers of CD45+CD8+ cells. G, Representative flow cytometry plots for CD8 versus IFNγ within a CD45+CD8+ gate and numbers of CD45+CD8+IFNγ+ cells. Values inside the plots represent the percentages from the CD45+CD8+ gate. H, Relative expression of perforin 1 and granzyme B mRNA. The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM. *, P < 0.05; **, P < 0.01.

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    Figure 6.

    Asb2α was expressed in Th2 cells and its loss impeded IL4 expression in Th2 cells. Naïve CD4+ T cells from ctrl and cKO mice were polarized ex vivo toward Th1 or Th2 and analyzed by flow cytometry and qRT-PCR. A, Relative expression of Gata3 and Tbet/Tbx21 mRNA. B, Data represent the percentages of Tbet+ and IFNγ+ in CD4+ cells. C, Data represent the percentages of Gata3+ in CD4+ cells. D, Data show representative flow cytometry plots for CD4 versus IL4, the percentages of IL4+ in CD4+ cells, and the IL4 geoMFI in CD4+ cells. Values inside the plots represent the percentages of IL4+ in CD4+cells. Naïve CD4+ T cells from control (ctrl) and cKO mice were polarized ex vivo toward Treg or Th17 and analyzed by flow cytometry. E, Data represents the percentage of FoxP3+ or IL10+ in CD4+ cells. F, Data represents the percentage of RORγt+ or IL17A+ in CD4+ cells. The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM. *, P < 0.05.

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    Figure 7.

    Deletion of Asb2 in Th2 cells attenuated colitis-associated tumorigenesis in mice by reducing the tumor-promoting effects of Th2 cells and enhancing the tumor-inhibiting effects of Th1 cells. Control (Ctrl) and/or cKO mice were injected with AOM, subsequently treated with three cycles of DSS, and analyzed 69 days after AOM injection (A–C, F–I). Transfer of wild-type (WT) CD45.1 Th2 cells to cKO mice promoted tumor growth. Mice were injected intravenously with Th2 cells differentiated from wild-type CD4+ cells 41, 48, and 62 days after AOM treatment. Representative images of colons (A), tumor loads in the colon (B), and enumerations of total tumor burden and of tumors following classification according to their size (C). Control (ctrl) and cKO mice were treated with AOM and DSS and the cells isolated from colons 43 (d43) after AOM injection were analyzed by flow cytometry and qRT-PCR. Data represent the numbers of CD45+IFNγ+ cells (D) and the relative expression of Ifnγ mRNA (E). IFNγ signaling is essential for protection of cKO mice against colitis-associated colorectal cancer progression. Mice were injected intraperitoneally with anti-IFNγ neutralizing antibodies or control IgG every 4 days after the second DSS cycle. Representative image of colons (F), tumor loads in the colon (G), and enumerations of total tumor burden and of tumors following classification according to their size (H) and representative colon sections stained with alcian blue and nuclear fast red (I). In A and F, scale bars = 0.5 cm. In I, scale bar = 200 μm. The numbers of independent biological repeats are indicated in italics. Data are represented as mean ± SEM. *, P < 0.05.

Additional Files

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    • Supplementary Figure legends - Supplementary Figure legends
    • Figure S1 - Figure S1 shows the numbers of dendritic cells, macrophages and B cells in the colon, and the numbers of dendritic cells in the mesenteric lymph nodes of control and cKO mice treated with AOM and DSS.
    • Figure S2 - Figure S2 shows the numbers of γÎ' T, IFN-γ+ γÎ' T, NK and IFN-γ+ NK cells in the colon of control and cKO mice treated with AOM and DSS.
    • Figure S3 - Figure S3 shows the numbers of IL-17A+ or FoxP3+IL-10+ in CD4+ cells in the spleen, mesenteric lymph nodes and colon of untreated control and cKO mice.
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Cancer Immunology Research: 7 (8)
August 2019
Volume 7, Issue 8
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The E3 Ubiquitin Ligase Asb2α in T Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer
Camille A. Spinner, Isabelle Lamsoul, Arnaud Métais, Chanaëlle Febrissy, Christel Moog-Lutz and Pierre G. Lutz
Cancer Immunol Res August 1 2019 (7) (8) 1332-1344; DOI: 10.1158/2326-6066.CIR-18-0562

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The E3 Ubiquitin Ligase Asb2α in T Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer
Camille A. Spinner, Isabelle Lamsoul, Arnaud Métais, Chanaëlle Febrissy, Christel Moog-Lutz and Pierre G. Lutz
Cancer Immunol Res August 1 2019 (7) (8) 1332-1344; DOI: 10.1158/2326-6066.CIR-18-0562
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