scholarly journals The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment

2015 ◽  
Vol 1 (10) ◽  
pp. e1500845 ◽  
Author(s):  
Madhav D. Sharma ◽  
Rahul Shinde ◽  
Tracy L. McGaha ◽  
Lei Huang ◽  
Rikke B. Holmgaard ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phosphatase And Tensin Homolog ◽  
Effector Cells ◽  
Multiple Tumor ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Immunosuppressive Tumor Microenvironment ◽  
Specialized Form ◽  
Tumor Types ◽  
Inflammatory Milieu

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.

scholarly journals Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1525 ◽  
Author(s):  
Geny Piro ◽  
Carmine Carbone ◽  
Luisa Carbognin ◽  
Sara Pilotto ◽  
Chiara Ciccarese ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cancer Immunoediting ◽  
Multiple Tumor ◽  
Cellular Processes ◽  
Tensin Homolog ◽  
Future Clinical Practice ◽  
Cancer Intervention

Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN’s role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice.

scholarly journals CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiakang Jin ◽  
Jinti Lin ◽  
Ankai Xu ◽  
Jianan Lou ◽  
Chao Qian ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Types ◽  
Host Cells ◽  
Specific Cell ◽  
Tumor Patients ◽  
Multiple Tumor ◽  
Inflammatory Monocytes ◽  
Immunosuppressive Cell ◽  
Tumor Types

Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes.

scholarly journals Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

2019 ◽  
Vol 8 (9) ◽  
pp. 1472 ◽  
Author(s):  
Sireesha Upadhrasta ◽  
Lei Zheng
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Types ◽  
Cancer Immunotherapies ◽  
Immune Defects ◽  
Made In

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic “cold” tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the “defects” in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects.

Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 63-63
Author(s):  
Jason Zhu ◽  
Sarabjot Pabla ◽  
Matthew Labriola ◽  
Rajan T. Gupta ◽  
Shannon McCall ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Standard Of Care ◽  
Reference Population ◽  
Gene Signature ◽  
Multiple Tumor ◽  
Markers Of Inflammation ◽  
Expert Radiologist ◽  
Chi Squared ◽  
Ffpe Tumor ◽  
Tumor Types

63 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high Teffhigh/PD-L1+ are more likely to respond to ICI. Here, we use this Teff gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related Teff status. Teff status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with Teffhigh/low separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as > 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, Teff gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as Teffhigh and 33 patients were classified as Tefflow. 6-month DC was 61% (22/36) in the Teffhigh cohort and 36% (12/33) in the Tefflow cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.

scholarly journals Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianyu He ◽  
Xiaoyun Zhang ◽  
Jianyu Hao ◽  
Shigang Ding
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Malignant Tumors ◽  
Biological Effects ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
And Migration

The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.

scholarly journals A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

2018 ◽  
Author(s):  
Taylor L. Mighell ◽  
Sara Evans-Dutson ◽  
Brian j. O’Roak
Keyword(s):  
Phosphatase Activity ◽  
Autism Spectrum ◽  
Saturation Mutagenesis ◽  
Single Amino Acid ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Functional Scores

ABSTRACTPhosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16×10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.

scholarly journals PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy

2020 ◽  
Vol 21 (15) ◽  
pp. 5337 ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Italia Falcone ◽  
Ludovica Ciuffreda ◽  
Gianluigi Ferretti ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Predictive Biomarkers ◽  
Point Of View ◽  
Solid Cancer ◽  
Host Immune System ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
And Function ◽  
Promising Development

Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy.

scholarly journals Oxidative Inactivation of the Lipid Phosphatase Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) as a Novel Mechanism of Acquired Long QT Syndrome

2010 ◽  
Vol 286 (4) ◽  
pp. 2843-2852 ◽  
Author(s):  
Xiaoping Wan ◽  
Adrienne T. Dennis ◽  
Carlos Obejero-Paz ◽  
Jeffrey L. Overholt ◽  
Jorge Heredia-Moya ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Long Qt ◽  
Phosphatase And Tensin Homolog ◽  
Oxidative Inactivation ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Acquired Long Qt Syndrome ◽  
Qt Syndrome
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