Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

Hargadon, Kristian M.

doi:10.3390/jcm5090076

Cited by 45 publications

(35 citation statements)

References 158 publications

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“…In addition, it was aberrantly activated in the late-stages of tumorigenesis and the dysregulation of TGFβ1 signaling pathway contributed to various aspects of cancer progression [36,37] . Recently, studies indicated that TGFβ1 greatly participated in numerous immune regulatory functions, such as tumor immune suppression and escape [38] . It was also signi cantly associated with the function of kinds of TICs, such as tumor-associated macrophages [39] , dendritic cells [40,41] , neutrophils [42] , T cells [43] and natural killer cells [44] .…”

Section: Discussionmentioning

confidence: 99%

TGFβ1: an Indicator for Tumor Immune Microenvironment (TIME) of Colon Cancer from a Comprehensive Analysis of TCGA

Wang

Wang²,

et al. 2020

Preprint

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Background: Tumor microenvironment (TME) and tumor-infiltrating immune cells (TIC) greatly participated in the genesis and development of colon cancer (CC). However, there are few researches exploring the dynamic modulation of TME. Methods: In our study, we analyzed the proportion of immune/stromal component and TIC in TME of 473 CC samples and 41 normal samples from The Cancer Genome Atlas (TCGA) database through ESTIMATE and CIBERSORT algorithm. Correlation analysis was carried out to evaluate the association between immune/stromal component in TME and clinicopathological characteristics of CC patients. The difference analysis was performed to obtain the differentially expressed genes (DEGs). These DEGs were further analyzed by gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, protein–protein interaction (PPI) network construction and COX regression analysis. Transforming growth factor β1 (TGFβ1) was finally overlapping from the above analysis. Furthermore, TGFβ1 was analyzed by paired analysis, Gene Set Enrichment Analysis (GSEA). The intersection between the difference analysis and correlation analysis was also conducted to learn the association between TGFβ1 and TICs.Results: Our result showed that immune component in TME was negatively related with the stages of CC. GO and KEGG enrichment analysis revealed that 1110 DEGs obtained from difference analysis were mainly enriched in immune-related activities. The intersection analysis between PPI network and COX regression analysis indicted that TGFβ1 was significantly associated with the communication of genes in PPI network and the Hazard Ratio (HR) of CC patients’ survival. In addition, TGFβ1 was up-regulated in the tumor samples and significantly related with poor prognosis of CC patients. Further GSEA suggested that genes in TGFβ1 up-regulated group were primarily enriched in immune-related activities and the function of TGFβ1 might depend on the communications with TICs, including T cells CD4 naïve and T cells regulatory (Tregs). Conclusions: The expression of TGFβ1 might be an indicator for tumor immune microenvironment (TIME) of CC and sever as a prognostic factor of CC. Drugs targeting TGFβ1 might be a potential immunotherapy for CC patients in the future.

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Section: Discussionmentioning

confidence: 99%

TGFβ1: an Indicator for Tumor Immune Microenvironment (TIME) of Colon Cancer from a Comprehensive Analysis of TCGA

Wang

Wang²,

et al. 2020

Preprint

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“…Further inhibitory mechanisms include ownregulation of costimulatory molecules thus limiting CTL activation, and secretion of immune-modulating factors. TGF-β, for example, promotes regulatory functions in dendritic cells and macrophages and directly inhibits T cell function 93 . Restoration of anti-tumor immunity via engineering antigen-specific T cells that are resistant to TGF-β is one hypothesis that is currently being explored (NCT00368082) 94 .…”

Section: The Limits Of Success For Adoptive T Cell Therapymentioning

confidence: 99%

Cell therapies for hematological malignancies: don't forget non-gene-modified t cells!

Grant

Bollard

2018

Blood Reviews

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Cell therapy currently performs an important role in the treatment of patients with various hematological malignancies. The response to the cell therapy is regulated by multiple factors including the patient's immune system status, genetic profile, stage at diagnosis, age, and underlying disease. Cell therapy that does not require genetic manipulation can be mediated by donor lymphocyte infusion strategies, selective depletion in the post-transplant setting and the ex vivo expansion of antigen-specific T cells. For hematologic malignancies, cell therapy is contributing to enhanced clinical responses and overall survival and the immune response to cell therapy is predictive of response in multiple cancer types. In this review we summarize the available T cell therapeutics that do not rely on gene engineering for the treatment of patients with blood cancers.

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“…Increased expression of TGFβ1 is a particular feature of the immunosuppressive tumor microenvironment (4) and has been studied extensively as part of a prospective clinical trial (7). During tumor progression, it becomes a stimulatory molecule that promotes immune evasion, growth, invasion, and metastasis by tumor cells (8).…”

Section: Introductionmentioning

confidence: 99%

“…Over the past few decades, the clinical therapeutic regimen for ccRCC has transitioned from a non-specific immune approach to immunotherapeutic strategies. With the clinical application of immunotherapy agents, such as nivolumab (anti-PD-1), the survival of patients with 7 infiltration as stromal and immune scores, and combined the stromal and immune scores as the ESTIMATE score (16).…”

Section: Introductionmentioning

confidence: 99%

Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA

Geng

Chen

et al. 2020

Cancer Immunology Research

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Dysfunction in T-cell antitumor activity contributes to the tumorigenesis, progression, and poor outcome of clear cell renal cell carcinoma (ccRCC), with this dysfunction resulting from high expression of programmed cell death-1 (PD-1) in T cells. However, the molecular mechanisms maintaining high PD-1 expression in T cells have not been fully investigated in ccRCC. Here, we describe a mechanism underlying the regulation of PD-1 at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between transforming growth factor beta 1 (TGFB1) and PDCD1 in ccRCC samples. The mechanism underlying the regulation of PD-1 mRNA was then investigated in vitro and in vivo using syngeneic tumor models. We also observed that TGFβ1 had prognostic significance in ccRCC patients, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFβ1 activated P38 and induced the phosphorylation of Ser 10 on H3, which recruited p65 to increase SRSF3 and SRSF5 expression in T cells. As a result, the half-life of PD-1 mRNA in T cells was prolonged. SRSF3 coordinated with NXF1 to induce PD-1 mRNA extranuclear transport in T cells. We then demonstrated that TGFβ1 could induce SRSF3 expression to restrict the antitumor activity of T cells, which influenced immunotherapy outcomes in ccRCC mouse models. Our findings highlight that tumor-derived TGFβ1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.

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Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

Cited by 45 publications

References 158 publications

TGFβ1: an Indicator for Tumor Immune Microenvironment (TIME) of Colon Cancer from a Comprehensive Analysis of TCGA

TGFβ1: an Indicator for Tumor Immune Microenvironment (TIME) of Colon Cancer from a Comprehensive Analysis of TCGA

Cell therapies for hematological malignancies: don't forget non-gene-modified t cells!

Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA

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