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Journal ArticleDOI

Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

TL;DR: Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells.
About: This article is published in Gastroenterology.The article was published on 2013-11-01 and is currently open access. It has received 407 citations till now. The article focuses on the topics: Pancreatic stellate cell & Regulatory T cell.
Citations
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Journal ArticleDOI
TL;DR: The progress made to date and the remaining challenges in bringing CAF-targeted therapies to the clinic are highlighted and the relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment are highlighted.
Abstract: Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell–cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment. Cancer-associated fibroblasts (CAFs) are often the most abundant cell type in the tumour microenvironment. Here, Song and colleagues discuss how to target or harness these cells for cancer therapy. They highlight the progress made to date and the remaining challenges in bringing CAF-targeted therapies to the clinic.

879 citations

Journal ArticleDOI
TL;DR: Current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types are described.
Abstract: Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

463 citations

Journal ArticleDOI
TL;DR: How the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, is discussed, and how scientific advances may help overcome these hurdles are discussed.

453 citations


Cites background from "Activated Pancreatic Stellate Cells..."

  • ...Powell, 2015), and (3) PDA, in which endogenous T cell responses are rare (Emmrich et al., 1998; Ene-Obong et al., 2013; von Bernstorff et al., 2001)....

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  • ...…ovarian cancer, in which potentially beneficial T cell responses exist in a subset of patients, but have proven difficult to augment (Santoiemma and Powell, 2015), and (3) PDA, in which endogenous T cell responses are rare (Emmrich et al., 1998; Ene-Obong et al., 2013; von Bernstorff et al., 2001)....

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Journal ArticleDOI
TL;DR: A novel role of lactate is established in control of proinflammatory T cell motility and effector functions, which provides a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.
Abstract: Lactate has long been considered a “waste” by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.

447 citations

Journal ArticleDOI
01 Sep 2015-Gut
TL;DR: Recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour–stroma with translational implications for future therapy and clinical trial design.
Abstract: Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.

422 citations

References
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Journal ArticleDOI
TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

31,015 citations

Journal ArticleDOI
29 Sep 2006-Science
TL;DR: In situ analysis of tumor-infiltrating immune cells may be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
Abstract: The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.

5,536 citations

Journal ArticleDOI
25 Mar 2011-Science
TL;DR: A unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles is discussed.
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

5,026 citations


"Activated Pancreatic Stellate Cells..." refers background in this paper

  • ...To our knowledge, we identified for the first time that higher CD8þ T-cell infiltration in PDAC tumors correlates with better patient survival, a finding that provides evidence for antitumor CD8þ T-cell cancer immunoediting in human PDAC.(2) The PDAC stromal microenvironment is composed of activated myofibroblasts including aPSC, extracellular matrix, blood vessels, and various immune cells, and the individual contributions to tumor progression remain elusive....

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  • ...These findings in human PDAC compared with other PBDs, reported for the first time, are consistent with reduced infiltration of CD8þ cytotoxic T cells recently reported in the KPC mouse model of PDAC.8,22,23 B A SIC A N D TR A N SLA TIO N A L PA N C R EA S Differential Immune Cell Infiltrate in Stromal Subcompartments We next characterized the immune infiltrate within stromal subcompartments of PDAC and identified that cytotoxic effector T cells (CD8þ), Tregs (FoxP3þ), B cells (CD20þ), and natural killer cells (CD56þ) were significantly reduced in juxtatumoral compartments compared with the panstromal areas....

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  • ...Ourdata further show for thefirst time that ahigherCD8þ T-cell juxtatumoral infiltrate is associated with improved survival postsurgical resection as analyzed by X-Tile software (Figure 3 and Supplementary Table 5).17,25 Of interest, a lower juxtatumoral Treg (FoxP3þ) infiltrate also showed a prosurvival effect in patients with PDAC....

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  • ...To our knowledge, we identified for the first time that higher CD8þ T-cell infiltration in PDAC tumors correlates with better patient survival, a finding that provides evidence for antitumor CD8þ T-cell cancer immunoediting in human PDAC.2 The PDAC stromal microenvironment is composed of activated myofibroblasts including aPSC, extracellular matrix, blood vessels, and various immune cells, and the individual contributions to tumor progression remain elusive.26 The PDAC stroma has been classified into 2 compartments based on differential gene expression13,30: the juxtatumoral and panstromal compartments....

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  • ...Taken together, these data suggest an important role for stromal PSC/T-cell interaction and the CXCL12/CXCR4 axis in PDAC....

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Journal ArticleDOI
TL;DR: The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor.
Abstract: Background Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established. Methods We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction. Results CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent ...

3,048 citations

Journal ArticleDOI
12 Jun 2009-Science
TL;DR: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.
Abstract: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

2,831 citations


Additional excerpts

  • ...The paucity of functional vasculature close to the PDAC tumor cells (juxtatumoral) is well established.(24) Taken together, these observations strongly suggest a hitherto unreported PDAC-specific CD8þ T-cell trafficking defect within human PDAC tissues....

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