Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding.

Transcription factors normally regulate gene expression through their action at sites where they bind to DNA. However, the balance of activating and repressive functions that a transcription factor can mediate is not completely understood. Here, we showed that the transcription factor PU.1 regulated gene expression in early T cell development both by recruiting partner transcription factors to its own binding sites and by depleting them from the binding sites that they preferred when PU.1 was absent. The removal of partner factors Satb1 and Runx1 occurred primarily from sites where PU.1 itself did not bind. Genes linked to sites of partner factor "theft" were enriched for genes that PU.1 represses despite lack of binding, both in a model cell line system and in normal T cell development. Thus, system-level competitive recruitment dynamics permit PU.1 to affect gene expression both through its own target sites and through action at a distance.

SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells.

Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor ß (Tgf-ß) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.

Special AT-Rich Sequence-Binding Protein 1 Supports Survival and Maturation of Naive B Cells Stimulated by B Cell Receptors.

Epigenetic mechanisms underpin the elaborate activities of essential transcription factors in lymphocyte development. Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin remodeler that orchestrates the spatial and temporal actions of transcription factors. Previous studies have revealed the significance of SATB1 in T cell lineage. However, whether and how SATB1 controls B cell lineage development is yet to be clarified. In this study, we show that SATB1 is an important factor during splenic B cell maturation. By analyzing SATB1/Tomato reporter mice, we determined the dynamic fluctuation of SATB1 expression in the B cell lineage. Although SATB1 expression decreased to minimal levels during B cell differentiation in the bone marrow, it resurged markedly in naive B cells in the spleen. The expression was dramatically downregulated upon Ag-induced activation. Splenic naive B cells were subdivided into two categories, namely SATB1high and SATB1-/low, according to their SATB1 expression levels. SATB1high naive B cells were less susceptible to death and greater proliferative than were SATB1-/low cells during incubation with an anti-IgM Ab. Additionally, SATB1high cells tended to induce the expression of MHC class II, CD86, and CD83. Accordingly, naive B cells from B lineage-specific SATB1 conditional knockout mice were more susceptible to apoptosis than that in the control group upon anti-IgM Ab stimulation in vitro. Furthermore, conditional knockout mice were less capable of producing Ag-specific B cells after immunization. Collectively, our findings suggest that SATB1 expression increases in naive B cells and plays an important role in their survival and maturation.

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.

Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.

The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages.

How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence.

Immune Profile of the Nasal Mucosa in Patients with Cutaneous Leishmaniasis.

Localized skin lesions are characteristic of cutaneous leishmaniasis (CL); however, Leishmania (Viannia) species, which are responsible for most CL cases in the Americas, can spread systemically, sometimes resulting in mucosal disease. Detection of Leishmania has been documented in healthy mucosal tissues (conjunctiva, tonsils, and nasal mucosa) and healthy skin of CL patients and in individuals with asymptomatic infection in areas of endemicity of L (V) panamensis and L (V) braziliensis transmission. However, the conditions and mechanisms that favor parasite persistence in healthy mucosal tissues are unknown. In this descriptive study, we compared the cell populations of the nasal mucosa (NM) of healthy donors and patients with active CL and explored the immune gene expression signatures related to molecular detection of Leishmania in this tissue in the absence of clinical signs or symptoms of mucosal disease. The cellular composition and gene expression profiles of NM samples from active CL patients were similar to those of healthy volunteers, with a predominance of epithelial over immune cells, and within the CD45+ cell population, a higher frequency of CD66b+ followed by CD14+ and CD3+ cells. In CL patients with molecular evidence of Leishmania persistence in the NM, genes characteristic of an anti-inflammatory and tissue repair responses (IL4R, IL5RA, POSTN, and SATB1) were overexpressed relative to NM samples from CL patients in which Leishmania was not detected. Here, we report the first immunological description of subclinically infected NM tissues of CL patients and provide evidence of a local anti-inflammatory environment favoring parasite persistence in the NM.

Special AT-rich Sequence Binding-Protein 1 (SATB1) Correlates with Immune Infiltration in Breast, Head and Neck, and Prostate Cancer.

BACKGROUND SATB1 is essential in gene regulation and associates with T cell development. Aberrant SATB1 expression has been reported in various neoplasms. However, correlations between SATB1 and tumor immune infiltration and prognosis in malignancies still remains unclear. MATERIAL AND METHODS We used Oncomine and the Tumor Immune Estimation Resource database to explore the expression of SATB1 in cancers. In addition, Kaplan-Meier plotter, PrognoScan, and Gene Expression Profiling Interactive Analysis were also used to assess the effects of SATB1 on clinical prognosis. Furthermore, correlations between cancer immune infiltration and SATB1 were analyzed via Tumor Immune Estimation Resource. RESULTS The results demonstrated that SATB1 correlates with prognosis in different types of cancers, such as breast invasive carcinoma (BRAC), head and neck cancer (HNSC), and prostate adenocarcinoma (PRAD). Decreased expression of SATB1 was associated with poor overall and progression-free survival of BRAC patients with positive estrogen receptor (ER) as well as mutated TP53. In addition, B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells infiltration in BRAC, HNSC, and PRAD were also correlated with SATB1 expression level. Moreover, we found strong correlations between SATB1 and various immune markers for BRAC, HNSC, and PRAD. CONCLUSIONS In BRAC, HNSC, and PRAD patients, SATB1 has potential to serve as a prognostic indicator for predicting tumor immune infiltration and prognosis.

Divergent SATB1 expression across human life span and tissue compartments.

Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8+ T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.

Special AT-rich sequence binding protein 1 is required for maintenance of T cell receptor responsiveness and development of experimental autoimmune encephalomyelitis.

The genome organizer special AT-rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL-17- and IFN-γ-producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen-inducible SATB1 deletion system, SATB1cKO-ER-Cre mice, was used. Encephalitogenic T cells from MOG35-55-immunized SATB1cKO-ER-Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell-mediated autoimmune diseases.

SATB1 Plays a Critical Role in Establishment of Immune Tolerance.

Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer that is expressed by T cells. T cell development is severely impaired in SATB1 null mice; however, because SATB1 null mice die by 3 wk of age, the roles of SATB1 in T cell development have not been well clarified. In this study, we generated and analyzed SATB1 conditional knockout (cKO) mice, in which the SATB1 gene was deleted from all hematopoietic cells. T cell numbers were reduced in these mice, mainly because of a deficiency in positive selection at the CD4(+)CD8(+) double-positive stage during T cell development in the thymus. We also found that SATB1 cKO mice developed autoimmune diseases within 16 wk after birth. In SATB1 cKO mice, the numbers of Foxp3(+) regulatory T (Treg) cells were significantly reduced at 2 wk of age compared with wild-type littermates. Although the numbers gradually increased upon aging, Treg cells in SATB1 cKO mice were still less than those in wild-type littermates at adulthood. Suppressive functions of Treg cells, which play a major role in establishment of peripheral tolerance, were also affected in the absence of SATB1. In addition, negative selection during T cell development in the thymus was severely impaired in SATB1 deficient mice. These results suggest that SATB1 plays an essential role in establishment of immune tolerance.

Autoantibody to scaffold attachment factor B (SAFB): A novel connective tissue disease-related autoantibody associated with interstitial lung disease.

OBJECTIVE: To identify and characterize a novel connective tissue disease (CTD)-related autoantibody (autoAb) directed against scaffold attachment factor B (SAFB). METHODS: AutoAb specificity was analyzed using RNA and protein-immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. RESULTS: By immunoprecipitation assay, 10 sera reacted with a protein with a molecular weight of approximately 160 kDa. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that the Ab specifically recognized SAFB. Anti-SAFB Abs were detected in 2 of 646 patients with systemic sclerosis (SSc) (0.3%), 1 of 1570 patients with polymyositis/dermatomyositis (0.06%), 4 of 270 patients with interstitial lung disease (ILD) (1.5%), 1 of 43 patients with overlap syndrome (2.3%) and 2 patients with other diseases including primary Raynaud's disease and eosinophilic pneumonia. Five patients with anti-SAFB Abs had Raynaud's phenomenon and 3 had nail fold punctate hemorrhage. Of note, 8 of the 10 patients (80%) suffered from ILD. None of the patients with anti-SAFB Abs had pulmonary arterial hypertension, heart disease, or renal involvement. CONCLUSIONS: Anti-SAFB Ab is a novel CTD-related autoAb possibly associated with ILD.

Hematopoiesis in steady-state versus stress: self-renewal, lineage fate choice, and the conversion of danger signals into cytokine signals in hematopoietic stem cells.

Long-term hematopoietic stem cells (LT-HSCs) replenish the innate and adaptive immune compartments throughout life. Although significant progress has defined the major transcription factors that regulate lineage specification, the architectural proteins that globally coordinate DNA methylation, histone modification, and changes in gene expression are poorly defined. Provocative new studies establish the chromatin organizer special AT-rich binding protein 1 (Satb1) as one such global regulator in LT-HSCs. Satb1 is a nuclear organizer that partitions chromatin through the formation of cage-like structures. By integrating epigenetic and transcriptional pathways, Satb1 coordinates LT-HSC division, self-renewal, and lymphoid potential. Unexpected among the assortment of genes under Satb1 control in hematopoietic stem cells (HSCs) are cytokines, a finding that takes on additional importance with the provocative finding that short-term HSCs and downstream multipotent progenitors are potent and biologically relevant cytokine secretors during stress-mediated hematopoiesis. Together, these studies reveal a new mechanism of fate regulation and an unforeseen functional capability of HSCs.

Chromatin organizer SATB1 is an important determinant of T-cell differentiation.

T-cell development and differentiation is coordinated by a multitude of signaling molecules and transcription factors that impart distinct functional properties to progenitors. In this review, we focus on the role of the T lineage-enriched chromatin organizer and regulator SATB1 in T-cell differentiation. SATB1 mediates Wnt signaling by recruiting ß-catenin to its genomic targets and coordinates T helper type 2 (T(H)2) differentiation by positively regulating GATA-3. In contrast, maintenance of regulatory T cell (Treg) functions are dependent on inhibition of SATB1-mediated modulation of global chromatin organization. We discuss how regulation of the activity of SATB1 has a critical role in driving these two important differentiation pathways in T cells.

SATB1 is required for CD8 coreceptor reversal.

Intrathymic signals induce the differentiation of immature CD4(+)CD8(+) double positive (DP) thymocytes into mature CD4(+) or CD8(+) single positive (SP) T cells. The transcriptional mechanism by which CD8 lineage is determined is not fully understood. The best evidence, which favors the kinetic signaling/coreceptor reversal model, indicates that signaled DP thymocytes terminate CD8 transcription prior to their subsequent re-initiation of CD8 transcription and ultimate differentiation into CD8SP T cells. We and others have shown that CD8 lineage commitment is severely perturbed in mice in which expression of the transcription factor SATB1 is either conventionally knocked out or T cell-specifically knocked down. Here, we demonstrate that, as with normal thymocytes, cultured SATB1-deficient DP thymocytes inactivate CD8 coreceptor transcription following receipt of signals (PMA plus ionomycin) that mimic TCR-mediated positive selection. However, this terminated CD8 transcription is not re-initiated by signals (IL-7) conducive to CD8 differentiation in SATB1-deficient DP. We show that SATB1 specifically binds to a cis-regulatory element within the CD8 enhancer (E8(III)) known to be required for coreceptor reversal. A requirement in CD8 coreceptor reversal identifies SATB1 as an essential trans-regulator of CD8 lineage fate, whose action may be mediated via recruitment to the E8(III) DP enhancer.

NF-κB Signaling and IL-4 Signaling Regulate SATB1 Expression via Alternative Promoter Usage During Th2 Differentiation.

SATB1 is a genome organizer protein that is expressed in a lineage specific manner in CD4+ T-cells. SATB1 plays a crucial role in expression of multiple genes throughout the thymic development and peripheral differentiation of T cells. Although SATB1 function has been subjected to intense investigation, regulation of SATB1 gene expression remains poorly understood. Analysis of RNA-seq data revealed multiple transcription start sites at the upstream regulatory region of SATB1. We further demonstrated that SATB1 gene is expressed via alternative promoters during T-helper (Th) cell differentiation. The proximal promoter "P1" is used more by the naïve and activated CD4+ T-cells whereas the middle "P2" and the distal "P3" promoters are used at a significantly higher level by polarized T-helper cells. Cytokine and TCR signaling play crucial roles toward SATB1 alternative promoter usage. Under Th2 polarization conditions, transcription factor STAT6, which operates downstream of the cytokine signaling binds to the P2 and P3 promoters. Genetic perturbation by knockout and chemical inhibition of STAT6 activation resulted in the loss of P2 and P3 promoter activity. Moreover, chemical inhibition of activation of NF-κB, a transcription factor that operates downstream of the TCR signaling, also resulted in reduced P2 and P3 promoter usage. Furthermore, usage of the P1 promoter correlated with lower SATB1 protein expression whereas P2 and P3 promoter usage correlated with higher SATB1 protein expression. Thus, the promoter switch might play a crucial role in fine-tuning of SATB1 protein expression in a cell type specific manner.

Functional relevance of SATB1 in immune regulation and tumorigenesis.

The Special AT-rich Sequence Binding Protein 1 (SATB1) is a chromatin organiser and transcription factor which regulates numerous cellular processes such as differentiation, proliferation and apoptosis through effects on gene expression. SATB1 undergoes various post-translational modifications, which determine its interaction with co-activators and co-repressors to induce regulation of gene transcription. SATB1 is an identified oncogene, its increased expression is associated with poor prognosis in many cancers. This paper provides a review on SATB1-mediated immune responses and on its target genes in the context of tumorigenesis and tumour progression. Specifically, we discuss the role of SATB1 in tumour immunity, Epithelial to Mesenchymal Transition (EMT), metastasis and multidrug resistance. Therapeutic targeting of aberrant SATB1 may be an important strategy in the treatment of cancer.

SATB1 Defines a Subtype of Cutaneous CD30+ Lymphoproliferative Disorders Associated with a T-Helper 17 Cytokine Profile.

Cutaneous CD30+ lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was overexpressed and promoted malignant T-cell proliferation in a portion of CD30+ LPDs. Here, we investigated the expression pattern of SATB1 in CD30+ LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30+ LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30+ anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1+ cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1+ lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30+ LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30+ LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future.

Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.

An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development.

Rag1 and Rag2 gene expression in CD4(+)CD8(+) double-positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unknown. Here, we show that the ASE physically interacts with the distant Rag1 and Rag2 gene promoters in DP thymocytes, bringing the two promoters together to form an active chromatin hub. Moreover, we show that the ASE functions as a classical enhancer that can potently activate these promoters in the absence of the silencer or other locus elements. In thymocytes lacking the chromatin organizer SATB1, we identified a partial defect in Tcra gene rearrangement that was associated with reduced expression of Rag1 and Rag2 at the DP stage. SATB1 binds to the ASE and Rag promoters, facilitating inclusion of Rag2 in the chromatin hub and the loading of RNA polymerase II to both the Rag1 and Rag2 promoters. Our results provide a novel framework for understanding ASE function and demonstrate a novel role for SATB1 as a regulator of Rag locus organization and gene expression in DP thymocytes.

Identification of special AT-rich sequence binding protein 1 as a novel tumor antigen recognized by CD8+ T cells: implication for cancer immunotherapy.

BACKGROUND: A large number of human tumor-associated antigens that are recognized by CD8(+) T cells in a human leukocyte antigen class I (HLA-I)-restricted fashion have been identified. Special AT-rich sequence binding protein 1 (SATB1) is highly expressed in many types of human cancers as part of their neoplastic phenotype, and up-regulation of SATB1 expression is essential for tumor survival and metastasis, thus this protein may serve as a rational target for cancer vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Twelve SATB1-derived peptides were predicted by an immuno-informatics approach based on the HLA-A*02 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from HLA-A*02(+) healthy donors and/or HLA-A*02(+) cancer patients. The recognition of HLA-A*02(+) SATB1-expressing cancer cells was also tested. Among the twelve SATB1-derived peptides, SATB1(565-574) frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and cancer patients. Importantly, SATB1(565-574)-specific T cells recognized and killed HLA-A*02(+) SATB1(+) cancer cells in an HLA-I-restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified a novel HLA-A*02-restricted SATB1-derived peptide epitope recognized by CD8(+) T cells, which, in turn, recognizes and kills HLA-A*02(+) SATB1(+) tumor cells. The SATB1-derived epitope identified may be used as a diagnostic marker as well as an immune target for development of cancer vaccines.