Xie et al. report that aberrant ciliary redistribution of phospholipid PI(4,5)P2 and filament-actin are necessary for olfactory cilia disassembly and contribute to the pathogenesis of Bardet–Biedl syndrome. Image credit: Nemes Laszlo/Shutterstock.
Development of resistance to chemo- and immuno- therapies often occurs following treatment of melanoma brain metastasis (MBM). In this scenario, astrocytes cooperate towards MBM progression by upregulating secreted-factors, amongst which we found that monocyte chemoattractant protein-1 (MCP-1) and its receptors, CCR2 and CCR4, are overexpressed in activated astrocytes and in brain metastatic melanoma cells compared to primary lesions. We show that melanoma cells alter astrocytes-secretome and evoke MCP-1 expression and secretion, which in turn enhance vascular hyperpermeability and proliferation, migration, and invasion of CCR2-expressing melanoma cells, while inhibiting MCP-1 rescued this phenotype. Pharmacological or molecular inhibition of MCP-1/CCR2 in MBM mouse model activates an anti-tumor immune-mediated response as revealed by the enhanced infiltration of cytotoxic CD8+ T cells, attenuated immunosuppressive phenotype of tumor-associated macrophages, and reduced infiltration of regulatory T cells, leading to inhibition of MBM progression and prolonged survival. In addition, blocking this key target in MBM, improved the therapeutic response of anti-PD-1 immunotherapy, regardless of the tumor mutational load. These results show that the MCP-1/CCR2 axis polarizes the brain microenvironment towards an anti-inflammatory/pro-tumorigenic phenotype, highlighting the therapeutic relevance of this pathway as a potential immune checkpoint in MBM.
Sabina Pozzi, Anna Scomparin, Dikla Ben-Shushan, Eilam Yeini, Paula Ofek, Alessio D. Nahmad, Shelly Soffer, Ariel Ionescu, Antonella Ruggiero, Adi Barzel, Henry Brem, Thomas M. Hyde, Iris Barshack, Sanju Sinha, Eytan Ruppin, Tomer Weiss, Asaf Madi, Eran Perlson, Inna Slutsky, Helena F. Florindo, Ronit Satchi-Fainaro
Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data identify new and prior associated gestational age differences in distinct lung and neuronal cell populations when compared to existing single-cell and bulk RNA-Seq data. Comparative analyses found hundreds of genes coincidently induced in lung and amniotic fluid, and dozens in brain and amniotic fluid. This data enabled creation of computational models that accurately predicted lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Importantly, antenatal steroids induced off target gene expression changes in the brain, impinging upon synaptic transmission, neuronal and glial maturation, which could have long term consequences on brain development. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.
Augusto F. Schmidt, Daniel Schnell, Kenneth P. Eaton, Kashish Chetal, Paranthaman S. Kannan, Lisa A. Miller, Claire A. Chougnet, Daniel T. Swarr, Alan H. Jobe, Nathan Salomonis, Beena D. Kamath-Rayne
Lentiviral vector-based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I restricted T cell epitope of LCMV and CD40L induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble PD-1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in SAMHD1 knock-out mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.
Takuya Tada, Thomas D. Norton, Rebecca Leibowitz, Nathaniel R. Landau
BACKGROUND. New therapeutic combinations to improve the outcome of ovarian cancer patients are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer. METHODS. This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS). RESULTS. Thirty-five patients were enrolled. Patients had a mean 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with Poly (ADP-ribose) polymerase inhibitors (PARPi) and/or Bevacizumab. The MTD was 400mg. The most common AEs included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). Overall RR was 79.3% with a stable disease (SD) rate of 18% resulting in a clinical benefit rate of 96.6%. The PFS was 11.4 months. RR and PFS did not differ based on number of lines of prior chemotherapy or prior maintenance therapy. CONCLUSIONS. This work demonstrates the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease. TRIAL REGISTRATION. ClinicalTrials.gov NCT03056833. FUNDING. This investigator-initiated trial was supported by Novartis who provided drug and funds for trial execution.
Lan G. Coffman, Taylor J. Orellana, Tianshi Liu, Leonard G. Frisbie, Daniel Normolle, Kent Griffith, Shitanshu Uppal, Karen McLean, Jessica L. Berger, Michelle Boisen, Madeleine Courtney-Brooks, Robert P. Edwards, Jamie Lesnock, Haider Mahdi, Alexander Olawaiye, Paniti Sukumvanich, Sarah E. Taylor, Ronald Buckanovich
Cub domain-containing protein 1 (CDCP1) is a surface protein highly expressed on the surface of many cancer cells, however, the distribution of CDCP1 in normal tissues and its potential roles in non-tumor cells are poorly understood. We previously reported that CDCP1 interacts with CD6, a surface marker of T cells, suggesting that it is a novel immunoregulator, but the physiological significance of the newly discovered CDCP1-CD6 interaction remains unclear. In this report, we found that CDCP1 is present on both human and mouse retinal pigmented epithelial cells (RPEs), a component of the blood-retina barrier (BRB), using a new anti-CDCP1 monoclonal antibody that we developed. CDCP1 knockout (KO) mice on two different genetic backgrounds both developed significantly attenuated retinal T cell infiltration and uveitis after adoptive transfer of pre-activated pathogenic T cells in a model of autoimmune uveitis. We also found that tight junctions were severely disrupted with infiltrating T cells detected in the RPE flat mounts prepared from the WT but not CDCP1 KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE was upregulated by IFNγ in vitro and after EAU induction in vivo. CD6 stimulation induced significantly increased RPE barrier permeability of WT, but not CDCP1 knockdown (KD) RPE, and activated T cells migrated through the WT RPE monolayes more efficiently than the CDCP1 KD RPE monolayers. In addition, CD6 stimulation of WT, but not the CDCP1 KD RPEs, induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPEs interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis.
Lingjun Zhang, Nozha Borjini, Yu Lun, Sweta Parab, Gospel Enyindah-Asonye, Rupesh Singh, Brent A. Bell, Vera L. Bonilha, Andrei I. Ivanov, David A. Fox, Rachel R. Caspi, Feng Lin
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