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  • 1
    Online Resource
    Online Resource
    Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy
    Oxford University Press (OUP) ; 2018
    In:  Journal of Leukocyte Biology Vol. 103, No. 5 ( 2018-05-07), p. 799-805
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 103, No. 5 ( 2018-05-07), p. 799-805
    Abstract: Due to their cytotoxic activities, many anticancer drugs cause extensive damage to the intestinal mucosa and have antibiotic activities. Here, we show that cisplatin induces significant changes in the repertoire of intestinal commensal bacteria that exacerbate mucosal damage. Restoration of the microbiota through fecal-pellet gavage drives healing of cisplatin-induced intestinal damage. Bacterial translocation to the blood stream is correspondingly abrogated, resulting in a significant reduction in systemic inflammation, as evidenced by decreased serum IL-6 and reduced mobilization of granulocytes. Mechanistically, reversal of dysbiosis in response to fecal gavage results in the production of protective mucins and mobilization of CD11b+ myeloid cells to the intestinal mucosa, which promotes angiogenesis. Administration of Ruminococcus gnavus, a bacterial strain selectively depleted by cisplatin treatment, could only partially restore the integrity of the intestinal mucosa and reduce systemic inflammation, without measurable increases in the accumulation of mucin proteins. Together, our results indicate that reconstitution of the full repertoire of intestinal bacteria altered by cisplatin treatment accelerates healing of the intestinal epithelium and ameliorates systemic inflammation. Therefore, fecal microbiota transplant could paradoxically prevent life-threatening bacteremia in cancer patients treated with chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1002/JLB.5HI1117-446RR
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 2
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    Online Resource
    Butyrophilin 3A1 is a Dynamic T Cell Regulator in Ovarian Cancer
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 194.2-194.2
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 194.2-194.2
    Abstract: Ovarian carcinoma microenvironmental T cells exert clinically relevant pressure against malignant progression; however current immunotherapies rarely induce ovarian cancer regression. Here we investigate CD277-containing butyrophilin 3A1 (BTN3A1), a poorly investigated immunoregulatory pathway driven by myeloid and tumor cells in ovarian tumor beds. We show that BTN3A1 is overexpressed in ovarian cancer and is associated with a significant survival disadvantage in these patients (n=200). Concomitantly, ectopic expression of BTN3A1 on APCs inhibits αβ T cell proliferation and Th1 cytokine production. Proteomic analyses and binding assays demonstrate that BTN3A1 interacts with the CD45 phosphatase and elements of the TCR. Consequently, TCR ligation in the presence of BTN3A1 inhibits the segregation of CD45 from the immune synapse and blunts downstream signaling by antagonizing the phosphorylation of CD3Zeta, Lck, and Zap70. We developed fully human αCD277 antibodies which rescue αβ T cell proliferation and Th1 cytokine responses, while driving the infiltration of T cells into tumor beds, delaying ovarian tumor progression in novel BTN3A1+ humanized mice and xenograft studies. Paradoxically, αCD277 antibodies promote the activation of γδ T cells by driving a conformational transformation of BTN3A1. Thus, co-transfer of γδ and Ag-specific αβ T cells in the presence of αCD277 antibodies synergize to further impair malignant progression in vivo. Overall, we show that BTN3A1 drives αβ T cell dysfunction in ovarian cancer, while αCD277 antibodies transform this molecule from immunosuppressive to immunostimulatory by rescuing αβ T cells and activating γδ T cells, thus dynamically unleashing T cell-driven antitumor immunity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.194.2
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Immune pressure against ovarian cancer depends on antigen-specific TRM T cells
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 138.4-138.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 138.4-138.4
    Abstract: Conventional memory T cells classically include central memory T (TCM) cells, residing in lymphoid organs, and effector memory T (TEM) cells, circulating through various tissues. Recently, a novel population of memory T cells has gained interest, namely tissue resident memory T (TRM) cells, which persist in tissues and do not recirculate. It is described that these cells reside in human tumors playing a role in tumor-specific T-cell responses. We found by flow cytometry that between 50%–80% of the CD8+ T cells in human ovarian carcinomas are CD103+CD69+TRM cells. RNA-seq of TRM and their re-circulating counterparts from 7 different human carcinomas showed a very distinctive phenotype, characterized by co-upregulation of effector (GZMB, IFNG) and exhaustion (PD-1, TIM3) markers, along with transcription factors and signaling molecules likely involved in the acquisition of the TRM phenotype. Unexpectedly, we found very little overlap between the TCR repertoire of both populations in multiple tumors, and TRM T cells consistently showed significantly higher clonality. Tumor antigen-specific TRM T cells intratumorally transferred into syngeneic mice were more effective at delaying tumor growth compared with their tumor antigen-specific recirculating counterparts. Finally, both the acquisition and the maintenance of a TRM phenotype within the CD8 T cell compartment at tumor beds are dependent on exposure to tumor cognate antigen. Together, our data indicate that TRM CD8+ T cells, but not their CD103− counterparts, represent tumor antigen-specific effector lymphocytes actively exerting anti-tumor immune pressure in the ovarian cancer microenvironment.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.138.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    The chromatin organizer SATB1 governs the epigenetic repression of the co-inhibitory receptor PD-1 in T cells
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 56.8-56.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 56.8-56.8
    Abstract: Despite the importance of Programmed Cell Death-1 (PDCD1/PD-1) in inhibiting T-cell effector activity, the mechanisms regulating its expression in anti-tumor lymphocytes remain poorly defined. Here we show that the chromatin organizer Special AT-rich Sequence-Binding Protein-1 (Satb1) is required to restrain activation-induced PD-1 expression. We demonstrate that, mechanistically, Satb1 physically interacts with a nucleosome remodeling deacetylase (NuRD) complex, which it recruits to Pdcd1 regulatory regions. This molecular complex thus drives histone de-acetylation and results in PD-1 repression in T cells. Accordingly, T-cell-specific Satb1 deficiency results in a 40-fold increase in PD-1 expression. Intriguingly, tumor-derived Transforming growth factor (Tgf)-β decreases Satb1 expression in T cells through binding of Smad Family Member (Smad) proteins to the Satb1 promoter, while Smad also competes with Satb1/NuRD for binding to Pdcd1 enhancers, cooperatively unleashing PD-1 expression in a Satb1-dependent manner. Consequently, Satb1-deficient tumor-reactive T cells lose their effector activity more rapidly than wild-type T cells at PD-L1+ tumor beds, but these differences are abrogated by sustained PD-L1 blockade. Therefore, we demonstrate that Satb1 is an epigenetic controller of PD-1 expression, and that Tgf-β signaling contributes to T cell dysfunction within the tumor microenvironment by inhibiting Satb1-mediated repression of PD-1.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.56.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Satb1 deficiency licenses TFH-differentiation
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 138.22-138.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 138.22-138.22
    Abstract: T Follicular Helper cells (TFH) provide both co-stimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. However, is not clear how TFH differentiation is regulated. We found that deficiency of the chromatin organizer Satb1 results in increased TFH formation in CD4Cre+Satb1flx/flx mice through up-regulation of the canonical TFH markers ICOS and PD-1 and suppression of Foxp3+PD-1highCXCR5+ T follicular regulatory (TFR) cells as well. Accordingly, CD4Cre+Satb1flx/flx mice, or RAG1−/− mice transferred with Satb1-deficient CD4+ T cells showed a dramatic accumulation of CD4+CXCR5+PD-1high upon ovarian tumor challenge, compared to their Satb1+ counterparts, which was associated with reduced tumor growth. Importantly, intratumoral administration of Satb1-deficient CD4+ T cells re-directed to target ovarian cancer cells through chimeric receptors, but not their Satb1+ counterparts, induce the formation of Tertiary Lymphoid Structures in most tumors. Conclusion Satb1 controls three mechanisms relevant for TFH differentiation and, subsequently, antigen-specific humoral responses; namely, PD- 1 expression, ICOS de-repression and TFR formation. Our results suggest a novel role for Satb1 as a major regulator of TFH differentiation and TLS during tumor formation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.138.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
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    SATB1 as a novel therapeutic target for methyltransferase inhibitors against Cutaneous T Cell Lymphoma
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 154.8-154.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 154.8-154.8
    Abstract: Cutaneous T cell lymphoma (CTCL) is a clinically unmet need. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT rich sequence binding protein 1 (Satb1) induces a progressively fatal lymphoma characterized by mature, skin homing, Notch activated CD4 and CD8 T cells. Mechanistically, Satb1 restrains Stat5 phosphorylation and the expression of skin homing chemokine receptors in mature T cells. Notably, SUV39H1 and 2 methyltransferase dependent epigenetic repression of SATB1 is universally found in human Sezary Syndrome, but not other peripheral T cell malignancies. Accordingly, H3K27 and H3K9 trimethylation occlude the SATB1 promoter in Sezary cells. Inhibition of SUV39H1 and 2 methyltransferases with novel drugs, unlike EZH2 inhibition, restores SATB1 expression, selectively abrogating the growth of primary Sezary cells more effectively than Romidepsin. Therefore, SATB1 acts as a tumor suppressor in mature T cells upon NOTCH1 deregulation, and inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides and Sezary syndrome.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.154.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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