Journal Articles

Immune cell biology

Biology of T cells, professional antigen presenting cells and other immune cell subsets; antigen processing and presentation

Soluble SLAMF6 receptor induces strong CD8+ T cell effector function and improves anti-melanoma activity in vivo

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SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti-melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an anti-apoptotic effect on tumor infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more interferon gamma and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8+ T cells in comparable numbers to high doses of interleukin-2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported in vivo with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy.

Author Info: (1) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital galiteis@gmail.com. (2) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (3) Sharrett Institute of Oncology, Hadassah

Author Info: (1) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital galiteis@gmail.com. (2) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (3) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (4) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (5) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (6) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (7) Weizmann Institute of Science. (8) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (9) Compugen Ltd. (10) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (11) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (12) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital.

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High macrophage PD-L1 expression not responsible for T cell suppression

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Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mvarphis). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNgamma-driven PD-L1 expression increased markedly on PerC Mvarphis after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity.

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (4) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (5) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (6) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (7) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. Electronic address: riggs@rider.edu.

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NF-kappaB and the Transcriptional Control of Inflammation

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The NF-kappaB transcription factor was discovered 30 years ago and has since emerged as the master regulator of inflammation and immune homeostasis. It achieves this status by means of the large number of important pro- and antiinflammatory factors under its transcriptional control. NF-kappaB has a central role in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and autoimmunity, as well as diseases comprising a significant inflammatory component such as cancer and atherosclerosis. Here, we provide an overview of the studies that form the basis of our understanding of the role of NF-kappaB subunits and their regulators in controlling inflammation. We also describe the emerging importance of posttranslational modifications of NF-kappaB in the regulation of inflammation, and highlight the future challenges faced by researchers who aim to target NF-kappaB transcriptional activity for therapeutic benefit in treating chronic inflammatory diseases.

Author Info: (1) Rheumatoid Arthritis Pathogenesis Centre of Excellence, Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. (2) Centre for

Author Info: (1) Rheumatoid Arthritis Pathogenesis Centre of Excellence, Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. (2) Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. Electronic address: ruaidhri.carmody@glasgow.ac.uk.

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Immune Consequences of in vitro Infection of Human Peripheral Blood Leukocytes with Vesicular Stomatitis Virus

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BACKGROUND: Oncolytic vesicular stomatitis virus (VSV) can be delivered intravenously to target primary and metastatic lesions, but the interaction between human peripheral blood leukocytes (PBLs) and VSV remains poorly understood. Our study aimed to assess the overall immunological consequences of ex vivo infection of PBLs with VSV. METHODS: Phenotypic analysis of lymphocyte subsets and apoptosis were evaluated with flow cytometry. Caspase 3/7 activity was detected by luminescence assay. Virus release was evaluated in a murine cell line (L929). Gene expression and cytokine/chemokine secretion were assessed by real-time PCR and multiplex assay, respectively. RESULTS: Ex vivo infection of PBLs with VSV elicited upregulated expression of RIG-I, MDA-5, tetherin, IFITM3, and MxA. VSV infection triggered rapid differentiation of blood monocytes into immature dendritic cells as well as their apoptosis, which depended on caspase 3/7 activation. Monocyte differentiation required infectious VSV, but loss of CD14+ cells was also associated with the presence of a cytokine/chemokine milieu produced in response to VSV infection. CONCLUSIONS: Systemic delivery is a major goal in the field of oncolytic viruses. Our results shed further light on immune mechanisms in response to VSV infection and the underlying VSV-PBL interactions bringing hope for improved cancer immunotherapies, particularly those based on intravenous delivery of oncolytic VSV.

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

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T regulatory cells mediate immunosuppresion by adenosine in peripheral blood, sentinel lymph node and TILs from melanoma patients

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T regulatory cells (Tregs), involved in tumour tolerance, can generate Adenosine by CD39/CD73 surface enzymes, which identify four Tregs subsets: CD39(+)CD73(-) nTregs, CD39(+)CD73(+) iTregs, CD39(-)CD73(+) oTregs and CD39(-)CD73(-) xTregs. In melanoma patients, increased Tregs levels are detected in peripheral blood (PB), sentinel lymph node (SLN) and tumour infiltrating lymphocytes (TILs), but Adenosine role was not investigated yet. We examined total Tregs and Adenosine subsets in PB, SLN and TILs from melanoma patients (n = 32) and PB from healthy donors (HD; n = 10) by flow cytometry. Total Tregs significantly increased in stage III-IV patients PB, in SLN and TILs, as compared to HD/stage I-II patients. Tregs subsets analyses showed that: 1) PB nTregs significantly increased in SLN and decreased in TILs; 2) iTregs significantly increased in stage III-IV patients PB and further significantly increased in SLN and TILs; 3) PB oTregs and xTregs significantly decreased in SLN and TILs. Patients clinical features did not significantly influence total Tregs, except SLN excision order. Results confirmed Tregs role in melanoma progression and indicate Adenosine generation as a novel escape mechanism, being nTregs and iTregs increased in PB/SLN/TILs.

Author Info: (1) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata

Author Info: (1) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy. Electronic address: paola.digennaro@unifi.it. (2) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy. (3) Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. (4) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy. (5) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy. (6) Dept. Anatomic Pathology - Dermatopathology Section, Santa Maria Annunziata Hospital, Florence, Italy. (7) Dept. Surgery and Translational Medicine, Dermatology Section, University of Florence, Italy. (8) Plastic and Reconstructive Surgery Unit - Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Tuscan Tumour Institute (ITT) - Santa Maria Annunziata Hospital, Florence, Italy.

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SIRT1 and HIF1alpha signaling in metabolism and immune responses

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SIRT1 and HIF1alpha are regarded as two key metabolic sensors in cellular metabolism pathways and play vital roles in influencing immune responses. SIRT1 and HIF1alpha regulate immune responses in metabolism-dependent and -independent ways. Here, we summarized the recent knowledge of SIRT1 and HIF1alpha signaling in metabolism and immune responses. HIF1alpha is a direct target of SIRT1. Sometimes, SIRT1 and HIF1alpha cooperate or act separately to mediate immune responses. In innate immune responses, SIRT1 can regulate the glycolytic activity of myeloid-derived suppressor cells (MDSCs) and influence MDSC functional differentiation. SIRT1 can regulate monocyte function through NF-kappaB and PGC-1, accompanying an increased NAD(+) level. The SIRT1-HIF1alpha axis bridges the innate immune signal to an adaptive immune response by directing cytokine production of dendritic cells in a metabolism-independent manner, promoting the differentiation of CD4(+) T cells. For adaptive immune cells, SIRT1 can mediate the differentiation of inflammatory T cell subsets in a NAD(+)-dependent manner. HIF1alpha can stimulate some glycolysis-associated genes and regulate the ATP and ROS generations. In addition, SIRT1-and HIF1alpha-associated metabolism inhibits the activity of mTOR, thus negatively regulating the differentiation and function of Th9 cells. As immune cells are crucial in controlling immune-associated diseases, SIRT1-and HIF1alpha associated-metabolism is closely linked to immune-associated diseases, including infection, tumors, allergic airway inflammation, and autoimmune diseases.

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (2) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (3) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (4) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. Electronic address: liugw@bnu.edu.cn.

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Blockade of CCR5-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy in gastric cancer

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PURPOSE: Myeloid derived suppressor cells (MDSC) play an important role in tumor immune evasion and its level significantly increased in patients with gastric cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCR5 level in gastric cancer. MATERIALS AND METHODS: G-MDSC and M-MDSC from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. CCR5 ligand CCL5 was detected by ELISA. CCR5 was detected by real-time PCR, western blot and flow cytometry. Furthermore, the therapeutic effects of CCR5 blockade was assessed by the tumor model. RESULTS: CCR5 ligand, gene and protein expression of CCR5, and surface expression of CCR5 significantly increased in blood and tumor of tumor-bearing mice, suggesting MDSC may be attracted into the parenchyma by CCL5/CCR5. Anti-CCR5 treatment decreased G-MDSC and M-MDSC in the periphery and tumor. In addition, combination treatment enhanced CD4+ and CD8+ T cell infiltration and decreased the tumor burden of tumor-bearing mice. CONCLUSIONS: This study elucidated a possible association between MDSC subsets and CCR5, in addition to provide a new potential target to enhance the efficacy of immunotherapy in patients with gastric cancer.

Author Info: (1) a Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (2) b Department of

Author Info: (1) a Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (2) b Department of Surgery, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (3) b Department of Surgery, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (4) c Department of Pathology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (5) d Division of Gastroenterology and Department of Internal Medicine, Veterans Affairs Medical Center, Karmanos Cancer Institute, School of Medicine , Wayne State University , Detroit , MI , USA. (6) e Department of Surgery , Jingan Branch of Huashan Hospital, Fudan University , Shanghai , P.R. China.

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Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells

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Supramolecular peptide nanofibers are attractive for applications in vaccine development due to their ability to induce strong immune responses without added adjuvants or associated inflammation. Here, we report that self-assembling peptide nanofibers bearing CD4+ or CD8+ T cell epitopes are processed through mechanisms of autophagy in antigen-presenting cells (APCs). Using standard in vitro antigen presentation assays, we confirmed loss and gain of the adjuvant function using pharmacological modulators of autophagy and APCs deficient in multiple autophagy proteins. The incorporation of microtubule-associated protein 1A/1B-light chain-3 (LC3-II) into the autophagosomal membrane, a key biological marker for autophagy, was confirmed using microscopy. Our findings indicate that autophagy in APCs plays an essential role in the mechanism of adjuvant action of supramolecular peptide nanofibers.

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (2) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (3) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (4) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (5) Division of Surgical Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, RM 3035, New Brunswick, New Jersey 08903, United States. (6) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (7) Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, P.O. Box 20708, Houston, Texas 77030, United States.

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High-Dimensional Profiling of Tumor-Specific Immune Responses: Asking T Cells about What They "See" in Cancer

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The foundations of basic T-cell immunology and an understanding of the roles for T cells in controlling cancer have led to the remarkable yet inconsistent success of cancer immunotherapy. Because of these advances in cancer treatment, the need is urgent for biomarkers that can predict the efficacy of these treatments and for new therapeutic strategies for cases where currently available approaches are ineffective. Although our ability to profile heterogeneous cell populations in human blood or tissue samples has vastly improved in the past decade, identifying the cell subsets relevant to diseases, and to cancer particularly, remains a challenge. Given strong evidence for the implication of T cells specific for tumor-expressed antigens in various forms of effective immunotherapy, here, we focus on the utility, challenges, and techniques for the identification and profiling of these important cells. We review recent techniques that allow identifying and profiling of tumor-specific T cells. As these methods improve, we can expect more rapid progress in the rational design of novel cancer biomarkers and therapies based on antigen-specific T cells. Cancer Immunol Res; 6(1); 2-9. (c)2018 AACR.

Author Info: (1) Singapore Immunology Network, Agency for Science Technology and Research, Singapore. evan_newell@immunol.a-star.edu.sg. (2) Singapore Immunology Network, Agency for Science Technology and Research, Singapore

Author Info: (1) Singapore Immunology Network, Agency for Science Technology and Research, Singapore. evan_newell@immunol.a-star.edu.sg. (2) Singapore Immunology Network, Agency for Science Technology and Research, Singapore.

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Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer

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Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4(+)Foxp3(+) regulatory T (Treg) cells. Those Treg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Treg cells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2(+) Treg cells and more interferon-gamma-positive (IFN-gamma(+)) CD8(+) cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.

Author Info: (1) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Department of Research, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002

Author Info: (1) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Department of Research, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China. (2) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. (3) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (4) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (5) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (6) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (7) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. xchen@umac.mo oppenhej@mail.nih.gov. (8) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. xchen@umac.mo oppenhej@mail.nih.gov. Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

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