Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation

Roden, Anja C.; Moser, Michael T.; Tri, Samuel D.; Mercader, Maria; Kuntz, Susan M.; Dong, Haidong; Hurwitz, Arthur A.; McKean, David J.; Celis, Esteban; Leibovich, Bradley C.; Allison, James P.; Kwon, Eugene D.

doi:10.4049/jimmunol.173.10.6098

Cited by 232 publications

(182 citation statements)

References 59 publications

(71 reference statements)

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“…The DR4-transgenic mice described by Taneja et al produce both RF and anti-CCP antibodies and large amounts of the proinflammatory cytokines tumor necrosis factor ␣ (TNF␣) and interleukin-18 (IL-18). Furthermore, the female mice had a much stronger T cell response to the DR4-restricted peptide than did the male mice, which is consistent with a recent study showing that deprivation of androgen in mice increases the cellularity of primary and peripheral lymphoid organs and increases T cell proliferation (2).…”

Section: Maurizio Cutolosupporting

confidence: 90%

Sex and rheumatoid arthritis: Mouse model versus human disease

Cutolo¹

2007

Arthritis & Rheumatism

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Section: Maurizio Cutolosupporting

confidence: 90%

Sex and rheumatoid arthritis: Mouse model versus human disease

Cutolo¹

2007

Arthritis & Rheumatism

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“…Laboratory mice usually do not develop prostatitis even during aging because they are maintained in aseptic vivaria and fed with a standard laboratory dietary regimen. On the other hand, even though the infiltration of inflammatory cells into the prostate was observed when mice were subjected to alternate androgen deprivation and replacement (41,42), tissue damage such as the disruption or ulceration of acinar outlines and epithelial reactive hyperplasia that frequently are observed in human chronic prostatitis rarely occur. The model of prostatitis induced by CP9 bacterial infection complements these models but is not without limitations.…”

Section: Discussionmentioning

confidence: 99%

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Kwon¹,

Zhang²,

Ittmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

139

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Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER; mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten fl/fl ) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.prostate stem cells | cells-of-origin for cancer

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“…Also, tolerance to tumor antigens is regulated by testosterone, as androgen ablation in a mouse model of prostate cancer reversed CD4 T-cell tolerance to a prostate restricted tumor antigen (8). Similarly, castration of male mice before vaccination with prostate-specific antigens enhanced CD8 T-cell vaccine response in many studies (9,10). Patients undergoing androgen deprivation in prostate cancer had increased infiltration of T cells into benign and malignant prostate tissue (11).…”

mentioning

confidence: 99%

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

Kissick

Sanda

Dunn

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

241

169

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The hormonal milieu influences immune tolerance and the immune response against viruses and cancer, but the direct effect of androgens on cellular immunity remains largely uncharacterized. We therefore sought to evaluate the effect of androgens on murine and human T cells in vivo and in vitro. We found that murine androgen deprivation in vivo elicited RNA expression patterns conducive to IFN signaling and T-cell differentiation. Interrogation of mechanism showed that testosterone regulates T-helper 1 (Th1) differentiation by inhibiting IL-12-induced Stat4 phosphorylation: in murine models, we determined that androgen receptor binds a conserved region within the phosphatase, Ptpn1, and consequent up-regulation of Ptpn1 then inhibits IL-12 signaling in CD4 T cells. The clinical relevance of this mechanism, whereby the androgen milieu modulates CD4 T-cell differentiation, was ascertained as we found that androgen deprivation reduced expression of Ptpn1 in CD4 cells from patients undergoing androgen deprivation therapy for prostate cancer. Our findings, which demonstrate a clinically relevant mechanism by which androgens inhibit Th1 differentiation of CD4 T cells, provide rationale for targeting androgens to enhance CD4-mediated immune responses in cancer or, conversely, for modulating androgens to mitigate CD4 responses in disorders of autoimmunity.immunomodulation | cancer immunotherapy | prostate neoplasm

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Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation

Cited by 232 publications

References 59 publications

Sex and rheumatoid arthritis: Mouse model versus human disease

Sex and rheumatoid arthritis: Mouse model versus human disease

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

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