Philadelphia, PA, United States
Philadelphia, PA, United States

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Brusilovsky M.,Ben - Gurion University of the Negev | Radinsky O.,Ben - Gurion University of the Negev | Cohen L.,Ben - Gurion University of the Negev | Yossef R.,Ben - Gurion University of the Negev | And 5 more authors.
European Journal of Immunology | Year: 2015

NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PubMed | University of Minnesota, Hannover Medical School, Hebrew University of Jerusalem, Charité - Medical University of Berlin and 6 more.
Type: Journal Article | Journal: Blood | Year: 2015

Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.

Jan R.,The Research Institute of Fox Chase Cancer Center | Huang M.,The Research Institute of Fox Chase Cancer Center | Lewis-Wambi J.,The Research Institute of Fox Chase Cancer Center
Breast Cancer Research | Year: 2012

Introduction: Despite the benefits of endocrine therapies such as tamoxifen and aromatase inhibitors in treating estrogen receptor (ER) alpha-positive breast cancer, many tumors eventually become resistant. The molecular mechanisms governing resistance remain largely unknown. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Recent studies indicate that PEDF expression is significantly reduced in several tumor types, including breast cancer, and that its reduction is associated with disease progression and poor patient outcome. In the current study, we investigated the role of PEDF in the development of endocrine resistance in breast cancer.Methods: PEDF mRNA and protein levels were measured in several endocrine-resistant breast cancer cell lines including MCF-7:5C, MCF-7:2A, and BT474 and in endocrine-sensitive cell lines MCF-7, T47D, and ZR-75-1 using real-time PCR and western blot analyses. Tissue microarray analysis and immunohistochemistry were used to assess the PEDF protein level in tamoxifen-resistant breast tumors versus primary tumors. Lentiviruses were used to stably express PEDF in endocrine-resistant breast cancer cell lines to determine their sensitivity to tamoxifen following PEDF re-expression.Results: We found that PEDF mRNA and protein levels were dramatically reduced in endocrine-resistant MCF-7:5C, MCF-7:2A, and BT474 breast cancer cells compared with endocrine-sensitive MCF-7, T47D, and ZR-75-1 cells, and that loss of PEDF was associated with enhanced expression of pSer167ERα and the receptor tyrosine kinase rearranged during transfection (RET). Importantly, we found that silencing endogenous PEDF in tamoxifen-sensitive MCF-7 and T47D breast cancer cells conferred tamoxifen resistance whereas re-expression of PEDF in endocrine-resistant MCF-7:5C and MCF-7:2A cells restored their sensitivity to tamoxifen in vitro and in vivo through suppression of RET. Lastly, tissue microarray studies revealed that PEDF protein was reduced in ~52.4% of recurrence tumors (31 out of 59 samples) and loss of PEDF was associated with disease progression and poor patient outcome.Conclusion: Overall, these findings suggest that PEDF silencing might be a novel mechanism for the development of endocrine resistance in breast cancer and that PEDF expression might be a predictive marker of endocrine sensitivity. © 2012 Jan et al.; licensee BioMed Central Ltd.

PubMed | The Research Institute of Fox Chase Cancer Center
Type: | Journal: Advances in experimental medicine and biology | Year: 2013

Memory CD8 T cells play an essential role in controlling pathogenic infections. Therefore generating protective memory CD8 T cells by vaccination is an attractive strategy for preventing and treating a variety of human diseases. Understanding what comprises a protective memory CD8 T cell response will help optimize vaccine-induced CD8 T cell immunity. Here we discuss essential antiviral effector functions and highlight how recall expansion of memory CD8 T cells may affect the primary response.

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