Publications by authors named "Stephen E Ullrich"

57 Publications

CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade.

Cancer Discov 2018 09 16;8(9):1156-1175. Epub 2018 Jul 16.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. and studies demonstrate that CD38 inhibits CD8 T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8 T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205194PMC
September 2018

Catalase Inhibits the Formation of Mast Cell Extracellular Traps.

Front Immunol 2018 28;9:1161. Epub 2018 May 28.

Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, México City, Mexico.

Tuberculosis is one of the leading causes of human morbidity and mortality. (Mtb) employs different strategies to evade and counterattack immune responses persisting for years. Mast cells are crucial during innate immune responses and help clear infections inflammation or by direct antibacterial activity through extracellular traps (MCETs). Whether Mtb induce MCETs production is unknown. In this study, we report that viable Mtb did not induce DNA release by mast cells, but heat-killed Mtb (HK-Mtb) did. DNA released by mast cells after stimulation with HK-Mtb was complexed with histone and tryptase. MCETs induced with PMA and HK-Mtb were unable to kill live Mtb bacilli. Mast cells stimulated with HK-Mtb induced hydrogen peroxide production, whereas cells stimulated with viable Mtb did not. Moreover, MCETs induction by HK-Mtb was dependent of NADPH oxidase activity, because its blockade resulted in a diminished DNA release by mast cells. Interestingly, catalase-deficient Mtb induced a significant production of hydrogen peroxide and DNA release by mast cells, indicating that catalase produced by Mtb prevents MCETs release by degrading hydrogen peroxide. Our findings show a new strategy employed by Mtb to overcome the immune response through inhibiting MCETs formation, which could be relevant during early stages of infection.
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http://dx.doi.org/10.3389/fimmu.2018.01161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985745PMC
August 2019

Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy.

Biomaterials 2018 03 9;159:215-228. Epub 2018 Jan 9.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2018.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203960PMC
March 2018

Detection of Infiltrating Mast Cells Using a Modified Toluidine Blue Staining.

Methods Mol Biol 2017 ;1627:213-222

Cellular Photoimmunology Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School at The Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.

Mast cells are part of the immune system and characteristically contain histamine- and heparin-rich basophilic granules. While these cells are usually associated with allergy and anaphylaxis, they also promote wound healing and angiogenesis and confer protection against pathogens. The presence of these cells is sometimes indicative of a poor prognosis, especially in skin cancer, pancreatic cancer, and lymphoma. Toluidine blue staining of acid-fast granules is an established method for the identification and quantification of mast cells. Generating detailed information on the location of mast cells within tissues is problematic using this technique and often requires serial sections from adjacent tissue to be separately stained with hematoxylin and eosin (H&E). Staining serial sections is not always possible, particularly if the sample is very small or rare. In such cases, a method of simultaneously identifying and localizing mast cells in a tissue would be advantageous. Toluidine blue and H&E are not commonly combined because H&E includes repetitive washes in water, which may affect the efficacy of the aqueous-soluble toluidine blue. We have developed and tested a novel staining technique that integrates toluidine blue between hematoxylin and eosin in one simple procedure. This protocol works on both frozen and formalin-fixed, paraffin-embedded tissue and readily allows for the identification of purple-stained mast cells against a clean H&E background. This facilitates a more accurate localization and proper counting of mast cells in normal and affected tissue.
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http://dx.doi.org/10.1007/978-1-4939-7113-8_14DOI Listing
May 2018

Platelet activating factor-induced expression of p21 is correlated with histone acetylation.

Sci Rep 2017 02 3;7:41959. Epub 2017 Feb 3.

Department of Immunology and The Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Ultraviolet (UV)-irradiated keratinocytes secrete the lipid mediator of inflammation, platelet-activating factor (PAF). PAF plays an essential role in UV-induced immune suppression and skin cancer induction. Dermal mast cell migration from the skin to the draining lymph nodes plays a prominent role in activating systemic immune suppression. UV-induced PAF activates mast cell migration by up-regulating mast cell CXCR4 surface expression. Recent findings indicate that PAF up-regulates CXCR4 expression via histone acetylation. UV-induced PAF also activates cell cycle arrest and disrupts DNA repair, in part by increasing p21 expression. Do epigenetic alterations play a role in p21 up-regulation? Here we show that PAF increases Acetyl-CREB-binding protein (CBP/p300) histone acetyltransferase expression in a time and dose-dependent fashion. Partial deletion of the HAT domain in the CBP gene, blocked these effects. Chromatin immunoprecipitation assays indicated that PAF-treatment activated the acetylation of the p21 promoter. PAF-treatment had no effect on other acetylating enzymes (GCN5L2, PCAF) indicating it is not a global activator of histone acetylation. This study provides further evidence that PAF activates epigenetic mechanisms to affect important cellular processes, and we suggest this bioactive lipid can serve as a link between the environment and the epigenome.
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http://dx.doi.org/10.1038/srep41959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291204PMC
February 2017

Growth and metastasis of lung adenocarcinoma is potentiated by BMP4-mediated immunosuppression.

Oncoimmunology 2016;5(11):e1234570. Epub 2016 Sep 26.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer cells modulate the recruitment and function of inflammatory cells to create an immunosuppressive microenvironment that favors tumor growth and metastasis. However, the tumor-derived regulatory programs that promote intratumoral immunosuppression remain poorly defined. Here, we show in a Krasp53-based mouse model that bone morphogenetic protein-4 (BMP4) augments the expression of the T cell co-inhibitory receptor ligand PD-L1 in the mesenchymal subset of lung cancer cells, leading to profound CD8 T cell-mediated immunosuppression, producing tumor growth and metastasis. We previously reported in this model that BMP4 functions as a pro-tumorigenic factor regulated by miR-200 via GATA4/6. Thus, BMP4-mediated immunosuppression is part of a larger miR-200-directed gene expression program in tumors that promotes tumor progression, which could have important implications for cancer treatment.
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http://dx.doi.org/10.1080/2162402X.2016.1234570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139626PMC
September 2016

Listeria monocytogenes induces mast cell extracellular traps.

Immunobiology 2017 02 6;222(2):432-439. Epub 2016 Aug 6.

Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico; Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico. Electronic address:

Mast cells play an essential role in different immunological phenomena including allergy and infectious diseases. Several bacteria induce mast cell activation leading to degranulation and the production of several cytokines and chemokines. However, mast cells also have different microbicidal activities such as phagocytosis and the release of DNA with embedded granular proteins known as Mast Cell Extracellular Traps (MCETs). Although previous reports indicate that extracellular bacteria are able to induce MCETs little is known if intracellular bacteria can induce these structures. In this work, we evaluated MCETs induction by the intracellular bacteria Listeria monocytogenes. We found that mast cells released DNA after stimulation with L. monocytogenes, and this DNA was complexed to histone and tryptase. Before extracellular DNA release, L. monocytogenes induced modifications to the mast cell nuclear envelope and DNA was detected outside the nucleus. L. monocytogenes stimulated mast cells to produce significant amounts of reactive oxygen species (ROS) and blocking NADPH oxidase diminished DNA release by mast cells. Finally, MCETs showed antimicrobial activity against L. monocytogenes that was partially blocked when β-hexosaminidase activity was inhibited. These results show that L. monocytogenes induces mast cells to produce microbicidal MCETs, suggesting a role for mast cells in containing infection beyond the induction of inflammation.
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http://dx.doi.org/10.1016/j.imbio.2016.08.006DOI Listing
February 2017

Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer.

Prog Lipid Res 2016 07 9;63:14-27. Epub 2016 Apr 9.

Department of Immunology and The Center for Cancer Immunology Research, The University of Texas Graduate School for Biomedical Sciences at Houston, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.
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http://dx.doi.org/10.1016/j.plipres.2016.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975990PMC
July 2016

Serotonin signalling is crucial in the induction of PUVA-induced systemic suppression of delayed-type hypersensitivity but not local apoptosis or inflammation of the skin.

Exp Dermatol 2016 07 18;25(7):537-43. Epub 2016 Apr 18.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Psoralen and UVA (PUVA) has immunosuppressive and proapoptotic effects, which are thought to be responsible alone or in combination for its therapeutic efficacy. However, the molecular mechanism by which PUVA mediates its effects is not well understood. Activation of the serotonin (5-hydroxytryptamine, 5-HT) pathway has been suggested to be involved in the modulation of T-cell responses and found to mediate UVB-induced immune suppression. In particular, the activation of the 5-HT2A receptor has been proposed as one mechanism responsible for UV-induced immune suppression. We therefore hypothesized that 5-HT may play a role in PUVA-induced effects. The model of systemic suppression of delayed-type hypersensitivity (DTH) to Candida albicans was used to study immune function after exposure of C3H and KIT(W) (-Sh/W-Sh) mice to a minimal inflammatory dose of topical PUVA. The intra-peritoneal injection of the 5-HT2 receptor antagonist ketanserin or cyproheptadine or an anti-5-HT antibody immediately before PUVA exposure entirely abrogated suppression of DTH but had no significant effect on inflammation, as measured by swelling and cellular infiltration of the skin, and apoptosis as determined by the number of sunburn cells in C3H mice. Importantly, the systemic injection of 5-HT recapitulated PUVA immune suppression of DTH but did not induce inflammation or apoptosis in the skin. KIT(W) (-Sh/W-Sh) mice (exhibiting myelopoietic abnormalities, including lack of 5-HT-containing mast cells) were resistant to PUVA-induced suppression of DTH but not local skin swelling. Thus, this points towards a crucial role of 5-HT signalling in PUVA-induced immune suppression but not inflammation or apoptosis in situ in the skin.
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http://dx.doi.org/10.1111/exd.12990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927393PMC
July 2016

T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-γ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma.

Cell Rep 2015 Dec 10;13(11):2470-2479. Epub 2015 Dec 10.

Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address:

USP15 is a deubiquitinase that negatively regulates activation of naive CD4(+) T cells and generation of IFN-γ-producing T helper 1 (Th1) cells. USP15 deficiency in mice promotes antitumor T cell responses in a transplantable cancer model; however, it has remained unclear how deregulated T cell activation impacts primary tumor development during the prolonged interplay between tumors and the immune system. Here, we find that the USP15-deficient mice are hypersensitive to methylcholantrene (MCA)-induced fibrosarcomas. Excessive IFN-γ production in USP15-deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet(+) regulatory T cells and CD11b(+)Gr-1(+) myeloid-derived suppressor cells at tumor site. Mixed bone marrow adoptive transfer studies further reveals a T cell-intrinsic role for USP15 in regulating IFN-γ production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-γ, which promotes an immunosuppressive tumor microenvironment during MCA-induced primary tumorigenesis.
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http://dx.doi.org/10.1016/j.celrep.2015.11.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691552PMC
December 2015

Loss of c-Kit and bone marrow failure upon conditional removal of the GATA-2 C-terminal zinc finger domain in adult mice.

Eur J Haematol 2016 Sep 14;97(3):261-70. Epub 2016 Jan 14.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Heterozygous mutations in the transcriptional regulator GATA-2 associate with multilineage immunodeficiency, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The majority of these mutations localize in the zinc finger (ZnF) domains, which mediate GATA-2 DNA binding. Deregulated hematopoiesis with GATA-2 mutation frequently develops in adulthood, yet GATA-2 function in the bone marrow remains unresolved. To investigate this, we conditionally deleted the GATA-2 C-terminal ZnF (C-ZnF) coding sequences in adult mice. Upon Gata2 C-ZnF deletion, we observed rapid peripheral cytopenia, bone marrow failure, and decreased c-Kit expression on hematopoietic progenitors. Transplant studies indicated GATA-2 has a cell-autonomous role in bone marrow hematopoiesis. Moreover, myeloid lineage populations were particularly sensitive to Gata2 hemizygosity, while molecular assays indicated GATA-2 regulates c-Kit expression in multilineage progenitor cells. Enforced c-Kit expression in Gata2 C-ZnF-deficient hematopoietic progenitors enhanced myeloid colony activity, suggesting GATA-2 sustains myelopoiesis via a cell intrinsic role involving maintenance of c-Kit expression. Our results provide insight into mechanisms regulating hematopoiesis in bone marrow and may contribute to a better understanding of immunodeficiency and bone marrow failure associated with GATA-2 mutation.
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http://dx.doi.org/10.1111/ejh.12719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680037PMC
September 2016

Platelet-Activating Factor Induces Epigenetic Modifications in Human Mast Cells.

J Invest Dermatol 2015 Dec 28;135(12):3034-3040. Epub 2015 Aug 28.

Department of Immunology and The Center for Cancer Immunology Research, The University of Texas, MD Anderson Cancer Center, Houston, Texas, 77030, USA.

UV radiation-induced systemic immune suppression is a major risk factor for skin cancer induction. The migration of dermal mast cells from the skin to the draining lymph nodes has a prominent role in activating systemic immune suppression. UV-induced keratinocyte-derived platelet-activating factor (PAF) activates mast cell migration, in part by upregulating the expression of CXCR4 on the surface of mast cells. Others have indicated that epigenetic mechanisms regulate CXCR4 expression; therefore, we asked whether PAF activates epigenetic mechanisms in mast cells. Human mast cells were treated with PAF, and the effect on DNA methylation and/or acetylation was measured. PAF suppressed the expression of DNA methyltransferase (DNMT) 1 and 3b. On the other hand, PAF increased p300 histone acetyltransferase expression, and the acetylation of histone H3, which coincided with a decreased expression of the histone deacetylase HDAC2. Chromatin immunoprecipitation assays indicated that PAF treatment activated the acetylation of the CXCR4 promoter. Finally, inhibiting histone acetylation blocked p300 upregulation and suppressed PAF-induced surface expression of CXCR4. Our findings suggest a novel molecular mechanism for PAF, activation of epigenetic modifications. We suggest that PAF may serve as an endogenous molecular mediator that links the environment (UV radiation) with the epigenome.
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http://dx.doi.org/10.1038/jid.2015.336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648694PMC
December 2015

Mast cells are required for phototolerance induction and scratching abatement.

Exp Dermatol 2015 Jul 16;24(7):491-6. Epub 2015 Apr 16.

Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.

Dermal mast cells protect the skin from inflammatory effects of ultraviolet (UV) radiation and are required for UV-induced immune suppression. We sought to determine a potential mechanistic role of mast cells in reducing the sensitivity to UV radiation (i.e. phototolerance induction) through photohardening. We administered single UV exposures as well as a chronic UV irradiation regime to mast cell-deficient Kit(W-Sh/W-Sh) mice and their controls. The chronic irradiation protocol was similar to that given for prophylaxis in certain photodermatoses in humans. Compared to controls, UV-exposed Kit(W-Sh/W-Sh) mice were more susceptible to epidermal hyperplasia and dermal oedema which was linked to blood vessel dilation. Unexpectedly, Kit(W-Sh/W-Sh) mice exhibited an excessive scratching behaviour following broadband UVB plus UVA or solar simulated UV irradiation at doses far below their minimal skin-swelling dose. Protection from this UV-induced scratching phenotype was dependent on mast cells, as engraftment of bone marrow-derived cultured mast cells abated it entirely. Kit(W-Sh/W-Sh) mice were entirely resistant to phototolerance induction by photohardening treatment. Compared to controls, these mice also showed reduced numbers of regulatory T cells and neutrophils in the skin 24 h after UV irradiation. While it is well known that mast cell-deficient mice are resistant to UV-induced immune suppression, we have discovered that they are prone to develop photo-itch and are more susceptible to UV-induced epidermal hyperplasia and skin oedema.
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http://dx.doi.org/10.1111/exd.12687DOI Listing
July 2015

Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.

Nat Commun 2014 Oct 28;5:5241. Epub 2014 Oct 28.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Immunosuppression of tumour-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8(+) TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T-cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.
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http://dx.doi.org/10.1038/ncomms6241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212319PMC
October 2014

USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses.

Nat Immunol 2014 Jun 28;15(6):562-70. Epub 2014 Apr 28.

1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.

Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.
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http://dx.doi.org/10.1038/ni.2885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032322PMC
June 2014

TRAF3 regulates the effector function of regulatory T cells and humoral immune responses.

J Exp Med 2014 Jan 30;211(1):137-51. Epub 2013 Dec 30.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor-associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell-specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.
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http://dx.doi.org/10.1084/jem.20131019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892978PMC
January 2014

Intratumoral mast cells promote the growth of pancreatic cancer.

Oncoimmunology 2013 Oct 2;2(10):e25964. Epub 2013 Aug 2.

Department of Immunology; The University of Texas MD Anderson Cancer Center; Houston, TX USA ; Center for Cancer Immunology Research; The University of Texas MD Anderson Cancer Center; Houston, TX USA ; The University of Texas Graduate School of Biomedical Sciences at Houston; Houston, TX USA.

We have recently discovered that mast cells promote pancreatic tumorigenesis by exacerbating the cellular and extracellular signaling in the desmoplastic microenvironment. Our findings demonstrate for the first time that targeting mast cells can block the progression of pancreatic neoplasms and prolong the survival of tumor-bearing immunocompetent hosts.
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http://dx.doi.org/10.4161/onci.25964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862685PMC
October 2013

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Elife 2013 Nov 5;2:e00969. Epub 2013 Nov 5.

Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.
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http://dx.doi.org/10.7554/eLife.00969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814616PMC
November 2013

An essential role for platelet-activating factor in activating mast cell migration following ultraviolet irradiation.

J Leukoc Biol 2014 Jan 5;95(1):139-48. Epub 2013 Sep 5.

1.Unit 902, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

The UVB (290-320 nm) radiation in sunlight is responsible for inducing skin cancer. Exposure to UV radiation is also immunosuppressive, and the systemic immune suppression induced by UV is a well-recognized risk factor for cancer induction. As UVB radiation is absorbed within the upper layers of the skin, indirect mechanisms must play a role in activating systemic immune suppression. One prominent example is mast cell migration, which from the skin to the draining LN is an essential step in the cascade of events leading to immune suppression. What triggers mast cell migration is not entirely clear. Here, we tested the hypothesis that PAF, a lipid mediator of inflammation produced by the skin in response to UV exposure, is involved. Mast cell-deficient mice (Kit(W-sh/W-sh)) are resistant to the suppressive effect of UV radiation, and reconstituting mast cell-deficient mice with normal bone marrow-derived mast cells restores susceptibility to immunosuppression. However, when mast cells from PAFR-/- mice were used, the reconstituted mice were not susceptible to the suppressive effects of UV. Furthermore, PAFR-/- mice showed impaired UV-induced mast cell migration when compared with WT mice. Finally, injecting PAF into WT mice mimicked the effect of UV irradiation and induced mast cell migration but not in PAFR-/- mice. Our findings indicate that PAFR binding induces mast cells to migrate from the skin to the LNs, where they mediate immune suppression.
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http://dx.doi.org/10.1189/jlb.0811409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868193PMC
January 2014

Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer.

Cancer Res 2013 Jul 30;73(13):3927-37. Epub 2013 Apr 30.

Department of Immunology and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment, which includes cancer-associated fibroblasts [also known as pancreatic stellate cells (PSC)] and immune cells that provide a fibrotic niche that impedes successful cancer therapy. We have found that mast cells are essential for PDAC tumorigenesis. Whether mast cells contribute to the growth of PDAC and/or PSCs is unknown. Here, we tested the hypothesis that mast cells contribute to the growth of PSCs and tumor cells, thus contributing to PDAC development. Tumor cells promoted mast cell migration. Both tumor cells and PSCs stimulated mast cell activation. Conversely, mast cell-derived interleukin (IL)-13 and tryptase stimulated PSC proliferation. Treating tumor-bearing mice with agents that block mast cell migration and function depressed PDAC growth. Our findings suggest that mast cells exacerbate the cellular and extracellular dynamics of the tumor microenvironment found in PDAC. Therefore, targeting mast cells may inhibit stromal formation and improve therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-4479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702652PMC
July 2013

The immunologic revolution: photoimmunology.

J Invest Dermatol 2012 Mar 15;132(3 Pt 2):896-905. Epub 2011 Dec 15.

Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

UV radiation targets the skin and is a primary cause of skin cancer (both melanoma and nonmelanoma skin cancer). Exposure to UV radiation also suppresses the immune response, and UV-induced immune suppression is a major risk factor for skin cancer induction. The efforts of dermatologists and cancer biologists to understand how UV radiation exposure suppresses the immune response and contributes to skin cancer induction led to the development of the subdiscipline we call photoimmunology. Advances in photoimmunology have generally paralleled advances in immunology. However, there are a number of examples in which investigations into the mechanisms underlying UV-induced immune suppression reshaped our understanding of basic immunological concepts. Unconventional immune regulatory roles for Langerhans cells, mast cells, and natural killer T (NKT) cells, as well as the immune-suppressive function of lipid mediators of inflammation and alarmins, are just some examples of how advances in immunodermatology have altered our understanding of basic immunology. In this anniversary issue celebrating 75 years of cutaneous science, we provide examples of how concepts that grew out of efforts by immunologists and dermatologists to understand immune regulation by UV radiation affected immunology in general.
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http://dx.doi.org/10.1038/jid.2011.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279601PMC
March 2012

Induction of B-cell lymphoma by UVB radiation in p53 haploinsufficient mice.

BMC Cancer 2011 Jan 26;11:36. Epub 2011 Jan 26.

Department of Immunology and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Background: The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation.

Methods: UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling.

Results: UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression.

Conclusion: UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The induction of B cell lymphoma in UV-irradiated p53 heterozygous mice may provide a useful model for lymphoma development in humans.
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http://dx.doi.org/10.1186/1471-2407-11-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041776PMC
January 2011

Mast cell-derived IL-10 suppresses germinal center formation by affecting T follicular helper cell function.

J Immunol 2011 Jan 22;186(1):25-31. Epub 2010 Nov 22.

Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The most prevalent cancer diagnosed in the world is sunlight-induced skin cancer. In addition to being a complete carcinogen, UV radiation, the causative agent of skin cancer, induces immune suppression. Because UV-induced immune suppression is a well-recognized risk factor for skin cancer induction, it is crucial to understand the mechanisms underlying UV-induced immune suppression. Mast cells, which have recently emerged as immune regulatory cells, are particularly important in UV-induced immune suppression. UV exposure does not induce immune suppression in mast cell-deficient mice. We report that UV irradiation blocks germinal center (GC) formation, Ab secretion, and T follicular helper (Tfh) cell function, in part by altering the expression of transcription factors BCL-6 and BLIMP-1. No suppression of GC formation, Tfh cell IL-21 expression, or Ab secretion was observed in UV-irradiated mast cell-deficient (Kit(W-sh/W-sh)) mice. When mast cell-deficient mice were reconstituted with wild type mast cells, immune suppression was restored. Reconstituting the mast cell-deficient mice with bone marrow-derived mast cells from IL-10-deficient mice failed to restore the ability of UV radiation to suppress GC formation. Our findings demonstrate a function for mast cells, suppression of Tfh cell production, GC formation, and Ab production in vivo.
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http://dx.doi.org/10.4049/jimmunol.1001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059502PMC
January 2011

Langerhans cells serve as immunoregulatory cells by activating NKT cells.

J Immunol 2010 Oct 15;185(8):4633-40. Epub 2010 Sep 15.

Department of Immunology, Center for Cancer Immunology Research, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.

Ultraviolet exposure alters the morphology and function of epidermal Langerhans cells (LCs), which play a role in UV-induced immune suppression. It is generally believed that UV exposure triggers the migration of immature LCs from the skin to the draining lymph nodes (LNs), where they induce tolerance. However, because most of the previous studies employed in vitro UV-irradiated LCs, the data generated may not adequately reflect what is happening in vivo. In this study, we isolated migrating LCs from the LNs of UV-irradiated mice and studied their function. We found prolonged LC survival in the LNs of UV-irradiated mice. LCs were necessary for UV-induced immune suppression because no immune suppression was observed in LC-deficient mice. Transferring LCs from UV-irradiated mice into normal recipient animals transferred immune suppression and induced tolerance. We found that LCs colocalized with LN NKT cells. No immune suppression was observed when LCs were transferred from UV-irradiated mice into NKT cell-deficient mice. NKT cells isolated from the LNs of UV-irradiated mice secreted significantly more IL-4 than NKT cells isolated from nonirradiated controls. Injecting the wild-type mice with anti-IL-4 blocked the induction of immune suppression. Our findings indicate that UV exposure activates the migration of mature LC to the skin draining LNs, where they induce immune regulation in vivo by activating NKT cells.
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http://dx.doi.org/10.4049/jimmunol.1000246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950871PMC
October 2010

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence.

Cell Cycle 2010 Aug 16;9(16):3328-36. Epub 2010 Aug 16.

Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53(R172P) embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53(R172P) MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth.
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http://dx.doi.org/10.4161/cc.9.16.12688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041166PMC
August 2010

Two-way traffic on the bridge from innate to adaptive immunity.

J Invest Dermatol 2010 Jul;130(7):1773-5

Department of Immunology and the Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Conventional wisdom suggests that information is usually transmitted from the dendritic cell (DC) to the T cell. In this issue, Schwarz and Schwarz demonstrate that UV-induced T regulatory cells (Tregs) can influence the biology of naïve DC. They report that IL-10-secreting Tregs prime DC to activate additional Tregs when injected into naïve mice. It may be possible to use DCs that have been "educated" by Tregs to induce immune tolerance in vivo.
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http://dx.doi.org/10.1038/jid.2010.139DOI Listing
July 2010

Agents that reverse UV-Induced immune suppression and photocarcinogenesis affect DNA repair.

J Invest Dermatol 2010 May 15;130(5):1428-37. Epub 2009 Oct 15.

Department of Immunology and the Center for Cancer Immunology Research, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.

UV exposure induces skin cancer, in part, by inducing immune suppression. Repairing DNA damage, neutralizing the activity of cis-urocanic acid, and reversing oxidative stress abrogate UV-induced immune suppression and skin cancer induction, suggesting that DNA, UCA, and lipid photo-oxidation serve as UV photoreceptors. What is not clear is whether signaling through each of these different photoreceptors activates independent pathways to induce biological effects or whether there is a common checkpoint where these pathways converge. Here, we show that agents known to reverse photocarcinogenesis and photoimmune suppression, such as platelet-activating factor (PAF) and serotonin (5-HT) receptor antagonists, regulate DNA repair. Pyrimidine dimer repair was accelerated in UV-irradiated mice injected with PAF and 5-HT receptor antagonists. Nucleotide excision repair (NER), as measured by unscheduled DNA synthesis, was accelerated by PAF and 5-HT receptor antagonists. Injecting PAF and 5-HT receptor antagonists into UV-irradiated Xeroderma pigmentosum complementation group A-deficient mice, which lack the enzymes responsible for NER, did not accelerate photoproduct repair. Similarly, UV-induced formation of 8-oxo-deoxyguanosine was reduced by PAF and 5-HT receptor antagonists. We conclude that PAF and 5-HT receptor antagonists accelerate DNA repair caused by UV radiation, which prevents immune suppression and interferes with photocarcinogenesis.
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http://dx.doi.org/10.1038/jid.2009.329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855396PMC
May 2010

Mast cells mediate the immune suppression induced by dermal exposure to JP-8 jet fuel.

Toxicol Sci 2009 Nov 2;112(1):144-52. Epub 2009 Sep 2.

Department of Immunology and The Center for Cancer Immunology Research, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Applying jet propulsion-8 (JP-8) jet fuel to the skin of mice induces immune suppression. Applying JP-8 to the skin of mice suppresses T-cell-mediated immune reactions including, contact hypersensitivity (CHS) delayed-type hypersensitivity and T-cell proliferation. Because dermal mast cells play an important immune regulatory role in vivo, we tested the hypothesis that mast cells mediate jet fuel-induced immune suppression. When we applied JP-8 to the skin of mast cell deficient mice CHS was not suppressed. Reconstituting mast cell deficient mice with wild-type bone marrow derived mast cells (mast cell "knock-in mice") restored JP-8-induced immune suppression. When, however, mast cells from prostaglandin E(2) (PGE(2))-deficient mice were used, the ability of JP-8 to suppress CHS was not restored, indicating that mast cell-derived PGE(2) was activating immune suppression. Examining the density of mast cells in the skin and lymph nodes of JP-8-treated mice indicated that jet fuel treatment caused an initial increase in mast cell density in the skin, followed by increased numbers of mast cells in the subcutaneous space and then in draining lymph nodes. Applying JP-8 to the skin increased mast cell expression of CXCR4, and increased the expression of CXCL12 by draining lymph node cells. Because CXCL12 is a chemoattractant for CXCR4+ mast cells, we treated JP-8-treated mice with AMD3100, a CXCR4 antagonist. AMD3100 blocked the mobilization of mast cells to the draining lymph node and inhibited JP-8-induced immune suppression. Our findings demonstrate the importance of mast cells in mediating jet fuel-induced immune suppression.
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http://dx.doi.org/10.1093/toxsci/kfp181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769063PMC
November 2009

JP-8 induces immune suppression via a reactive oxygen species NF-kappabeta-dependent mechanism.

Toxicol Sci 2009 Mar 18;108(1):100-9. Epub 2008 Dec 18.

The Department of Immunology and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Applying jet fuel (JP-8) to the skin of mice induces immune suppression. JP-8-treated keratinocytes secrete prostaglandin E(2), which is essential for activating immune suppressive pathways. The molecular pathway leading to the upregulation of the enzyme that controls prostaglandin synthesis, cyclooxygenase (COX)-2, is unclear. Because JP-8 activates oxidative stress and because reactive oxygen species (ROS) turn on nuclear factor kappa B (NF-kappabeta), which regulates the activity of COX-2, we asked if JP-8-induced ROS and NF-kappabeta contributes to COX-2 upregulation and immune suppression in vivo. JP-8 induced the production of ROS in keratinocytes as measured with the ROS indicator dye, aminophenyl fluorescein. Fluorescence was diminished in JP-8-treated keratinocytes overexpressing catalase or superoxide dismutase (SOD) genes. JP-8-induced COX-2 expression was also reduced to background in the catalase and SOD transfected cells, or in cultures treated with N-acetylcysteine (NAC). When NAC was injected into JP-8-treated mice, dermal COX-2 expression, and JP-8-induced immune suppression was inhibited. Because ROS activates NF-kappabeta, we asked if this transcriptional activator played a role in the enhanced COX-2 expression and JP-8-induced immune suppression. When JP-8-treated mice, or JP-8-treated keratinocytes were treated with a selective NF-kappabeta inhibitor, parthenolide, COX-2 expression, and immune suppression were abrogated. Similarly, when JP-8-treated keratinocytes were treated with small interfering RNA specific for the p65 subunit of NF-kappabeta, COX-2 upregulation was blocked. These data indicate that ROS and NF-kappabeta are activated by JP-8, and these pathways are involved in COX-2 expression and the induction of immune suppression by jet fuel.
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http://dx.doi.org/10.1093/toxsci/kfn262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721654PMC
March 2009

Inhibition of photocarcinogenesis by platelet-activating factor or serotonin receptor antagonists.

Cancer Res 2008 May;68(10):3978-84

Department of Immunology and the Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT(2A)) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT(2A) to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT(2A) receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT(2A) receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT(2A) receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT(2A) receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-6132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394717PMC
May 2008