TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

Park, Benjamin V.; Freeman, Zachary T.; Ghasemzadeh, Ali; Chattergoon, Michael A.; Rutebemberwa, Alleluiah; Steigner, Jordana; Winter, Matthew E.; Huynh, Thanh V.; Sebald, Suzanne M.; Lee, Se Jin; Fan, Ping; Pardoll, Drew M.; Cox, Andrea L.

doi:10.1158/2159-8290.cd-15-1347

Cited by 214 publications

(177 citation statements)

References 69 publications

(82 reference statements)

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“…Consistent with a recent report (Park et al, 2016), we confirmed that translocated Smad proteins occupy crucial regulatory regions upstream of the Pdcd1 transcriptional start site in response to Tgf-β. Interestingly, we found that the segment of CR-C occupied by Satb1 overlaps with, or is adjacent to, the Smad protein binding site.…”

Section: Discussionsupporting

confidence: 92%

“…A recent report identified that Tgf-β-driven PD-1 expression is associated with binding of Smad3 to PD-1 promoter regions (Park et al, 2016). Our ChIP-PCR experiments confirmed that, in response to Tgf-β, Smad2/3 bind to CR-C , one of the conserved upstream regulatory regions hypersensitive to DNase I that control PD-1 expression in response to CD8 T cell activation (Lu et al, 2014; Oestreich et al, 2008) (Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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SUMMARY 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 β (Tgf-β) 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.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…It has been suggested that cancer‐derived TGF‐β play a critical role in immune suppression occurring in cancer patients. Similarly, it was reported that TGF‐β upregulated PD‐1 expression on T cells in cancer patients . In addition, PD‐1 induction through TCR activation was partially regulated by endogenous TGF‐β .…”

Section: Introductionmentioning

confidence: 61%

“…Blocking TGF‐β enhanced the CD8 + T cell‐mediated antitumor ability . TGF‐β was identified as an immune suppressor that increased PD‐1 expression on antigen‐specific CD8 + T cells in cancer . Furthermore, the major source of TGF‐β in tumor tissues was verified to be secreted by MDSCs in ESCC.…”

Section: Discussionmentioning

confidence: 97%

Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8⁺ T cell response in esophageal squamous cell carcinoma

Chen

Wang

et al. 2018

Intl Journal of Cancer

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PD‐1 is highly expressed on tumor‐infiltrated antigen‐specific T cells and limit the antitumor function. Blocking of PD‐1/PD‐L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE‐A3‐specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE‐A3‐specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE‐A3‐specific CD8+ T cells could lyse HLA‐A2+/MAGE‐A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD‐1 was highly expressed on dysfunctional antigen‐specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid‐derived suppressor cells (MDSCs) derived‐TGF‐β mediated PD‐1high expression on CD8+ T cells, which led to be resistance to PD‐1/PD‐L1 blockade in TME. Dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockades synergistically restored the function and antitumor ability of antigen‐specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE‐A3‐specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs‐derived TGF‐β increased PD‐1 expression on T cells and decreased the sensitivity to PD‐1/PD‐L1 blockade. Combining T cell‐based therapy with dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockade could be considered a promising strategy for cancer treatment.

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“…Rosa26 reporter mice (R26 EGFP ) were previously described (57) and were purchased from the Jackson Laboratory (catalog 012429). LoxP-targeted Smad2/3 mice were recently described as well (58). PCR genotyping used the primers Smad3 forward 5′-GTTTACTGGACTGAGGTTGGCTGTGGC-3′ and reverse 5′-GTACAGATTGGCCACTCCGGTCACTG-3′, which generated a 390-bp product recognizing loxP-targeted exons 2/3 and 287-bp WT fragments.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Khalil¹,

Kanisicak²,

Prasad³

et al. 2017

Journal of Clinical Investigation

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reverse transcribed using random oligo-dT primers and a Verso cDNA Synthesis Kit (Thermo Fisher, AB1453) according to the manufacturer's instructions. Real-time PCR was performed using SsoAdvanced SYBR Green (Bio-Rad, 6090), and Rpl7 expression was used for normalization. The following primer sets were used to identify transcripts: collagen 1a1, 5′-AATGGCACGGCTGTGTGCGA and 5′-AACGGGTCCCCTTG-GGCCTT; collagen 3a1, 5′-TCCCCTGGAATCTGTGAATC and 5′-TGAGTCGAATTGGGGAGAAT; periostin, 5′-ACGGAGCTCAGG-GCTGAAGATG and 5′-GTTTGGGCCCTGATCCCGAC.Cell death analysis. At 90% confluence, primary skin fibroblasts were treated with 200 nM staurosporine for 36 hours or vehicle (DMSO). Cell death was determined by the Muse Count & Viability Assay (Millipore, MCH100102) as previously described (62). Briefly, the medium was collected with the trypsin-liberated cells, which were centrifuged and washed twice with PBS and then incubated with the Muse Count & Viability reagent. The cells were then quantified on a Muse cell analyzer (Millipore) at 5,000 counts per sample.Statistics. One-way ANOVA with post hoc Tukey's honest significant difference (HSD) or Student's t test was used to determine statistical significance, depending on the type of data analyzed and number of comparisons. P values of less than 0.05 were considered statistically significant. Averaged data are presented with SEM to indicate variability.Study approval. Mice were observed daily and cages changed weekly by certified veterinary technicians at Cincinnati Children's Hospital Medical Center. Mice were also closely assessed for their well-being, monitored by adequate physical activity and food intake on a daily basis. Housing conditions and husbandry conformed to AAALAC standards as well as the standard guidelines from the NIH Office of Laboratory Animal Welfare (http://grants.nih.gov/grants/olaw/animal_use. htm). The institution also retains ongoing certification by AAALAC.

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TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

Cited by 214 publications

References 69 publications

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

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

Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8⁺ T cell response in esophageal squamous cell carcinoma

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

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TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

Cited by 214 publications

References 69 publications

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

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

Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8+ T cell response in esophageal squamous cell carcinoma

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

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Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8⁺ T cell response in esophageal squamous cell carcinoma