Aire Deficiency Promotes TRP-1–Specific Immune Rejection of Melanoma

Zhu, Meng Lei; Nagavalli, Anil; Su, Maureen A.

doi:10.1158/0008-5472.can-12-3781

Cited by 49 publications

(67 citation statements)

References 43 publications

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“…These therapies are utilized for their antiproliferative effects on breast cancer cells; however, they may have the unintended consequence of increasing AIRE transcription. Since AIRE limits the antitumor immune response against self antigens expressed by tumors (16,17), increasing AIRE transcription may tion or that the estrogen/ER complex may indirectly inhibit DNA demethylation. Evidence in support of the former comes from studies in breast cancer that suggest that ER may indeed positively regulate DNMTs (12).…”

Section: Discussionmentioning

confidence: 99%

Estrogen turns down “the AIRE”

Bakhru¹,

Su²

2016

Journal of Clinical Investigation

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C o m m e n t a r yAutoimmune disease: sex-dependent differencesThe incidence of autoimmune disease is increasing worldwide; therefore, the need to understand the basis of autoimmunity has taken on a new urgency. Progress in identifying genetic contributors to autoimmunity has been made through the study of monogenic autoimmune diseases. Such an approach has identified critical immuneregulatory genes, such as the autoimmune regulator (AIRE), which encodes a nuclear protein that functions as a key regulator of thymic central tolerance (reviewed in ref. 1). AIRE enforces self tolerance by promoting the promiscuous expression of tissue self-antigens (TSAs) within medullary thymic epithelial cells (mTECs), a nonhematopoietic, stromal cell population (Figure 1A). Presentation of these TSAs within the thymus results in negative selection of bone marrow-derived T cells, which recognize these TSAs with high affinity. In addition to eliminating autoreactive T cell clones within the thymus, AIRE also maintains self tolerance by diverting autoreactive T cells into the Treg lineage. AIRE is important for preventing autoimmune disease, as individuals with a complete loss of AIRE function develop the multiorgan autoimmune disease autoimmune polyendocrinopathy syndrome type 1 (APS1, which is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]). While genetics are a major factor that determines autoimmune disease predisposition, it is clear that sex also plays a defining role in disease development. The incidence of autoimmunity is skewed toward females for many autoimmune diseases, including Sjögren's disease, systemic lupus erythematosus (SLE), and autoimmune thyroid disease (reviewed in ref. 2). Remarkably, over 80% of those affected with these conditions are female, illustrating the strong influence of sex in disease predisposition. Multiple factors likely underlie this sex bias, including the distinct sex hormone profiles in females versus males. Accumulating evidence suggests that male androgen hormones are immune suppressive, while female estrogen hormones are immune activating. For instance, androgen increases the differentiation of immunoregulatory CD4+ T cells (3), whereas estrogen enhances survival of T cells in patients with autoimmunity (4). Thus, there is a plethora of evidence that sex hormones directly modulate T cells in the periphery.Early clues that sex hormones may also modulate thymic stromal populations, such as mTECs, came from elegant studies that utilized bone marrow chimeras (5, 6). These studies showed that thymic epithelial cells express estrogen receptor (ER) and androgen receptor (AR) and that expression of these hormone receptors in the stromal compartment is required for altering bone marrow-derived T cell subsets in the thymus (5, 6). In this issue, Dragin et al. confirm that sex hormones indeed act on receptors on thymic stromal cells to impinge upon T cell development within the thymus. Furthermore, this study demonstrates that sex hormones regulate AIRE expre...

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Section: Discussionmentioning

confidence: 99%

Estrogen turns down “the AIRE”

Bakhru¹,

Su²

2016

Journal of Clinical Investigation

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“…A dominant Aire G228W mutation results in partial loss of Aire function (17), and mice with one copy of this mutation (Aire GW/+ mice) have increased antimelanoma immunity (11). We used Aire GW/+ mice to test the hypothesis that Aire deficiency and peripheral checkpoint inhibition have additive effects in increasing antimelanoma immunity.…”

Section: Aire Deficiency Enhances Antimelanoma Effects Of Ctla-4 Blocmentioning

confidence: 99%

“…We next sought to delineate the cellular mechanism underlying enhanced antimelanoma immunity with combined Aire deficiency and CTLA-4 blockade. While it is known that Aire deficiency rescues melanoma-reactive CD4 + and CD8 + T cells from thymic deletion (10,11) donors into RAG -/-recipients, followed by s.c. B16 melanoma injection on day 7. Recipients were followed for tumor growth and survival.…”

Section: Aire Deficiency Enhances Antimelanoma Effects Of Ctla-4 Blocmentioning

confidence: 99%

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Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru¹,

Zhu²,

Wang³

et al. 2017

JCI Insight

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“…[1][2][3][4][5] mTECs express membrane either proteins normally expressed in the thymus and proteins expressed in peripheral organs, called tissue-specific antigens (TSAs). The transcription factor autoimmune regulator (AIRE) gene (NM_000383.3), by promoting the ectopic expression of thousands of genes encoding TSAs in mTECs, plays a fundamental role in the tolerance process.…”

Section: Introductionmentioning

confidence: 99%

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

et al. 2016

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The autoimmune regulator gene (AIRE) plays a fundamental role in tolerance by promoting the expression of tissue-specific antigens in medullary thymic epithelial cells (mTECs). Recently, AIRE expression was detected also in human keratinocytes and in tumors originating in stratified epithelia. Here, we tested whether AIRE is expressed in cancer cells. We analyzed AIRE expression in cancer cases from The Cancer Genome Atlas (TCGA) RNA-seq dataset and we found association with better outcome. AIRE protein expression was verified by immunohistochemistry in a cohort of 39 human breast cancer specimens and its prognostic relevance was confirmed in microarray-based gene expression data set NKI-295 and KM-Plotter. Both in the RNA-seq and gene expression datasets analyzed, AIRE expression was an independent strong prognostic factor for relapse-free survival (RFS), particularly in estrogen receptor-positive tumors. Enrichment of translation-related pathways was observed in AIRE-expressing tumors by Ingenuity Pathway Analysis and a significant increase of cells in G1 phase and activation of caspase cascades was induced by AIRE transfection in breast cancer luminal cell lines, suggesting that AIRE-induced over-translation of proteins lead to cycle arrest and apoptosis. These data are the first to identify AIRE expression in breast cancer and an association with prognosis.

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Aire Deficiency Promotes TRP-1–Specific Immune Rejection of Melanoma

Cited by 49 publications

References 43 publications

Estrogen turns down “the AIRE”

Estrogen turns down “the AIRE”

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

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