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Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14 ARF . Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies. The accumulation of senescent cells within tissues plays a role in numerous age-related pathologies. Yosef and Pilpel et al . demonstrate that the resistance of these cells to apoptosis is driven by upregulation of survival proteins, whose pharmacological inhibition triggers senescent cell elimination in mice.

Stress can induce cell surface expression of MHC-like ligands, including MICA, that activate NK cells. Human cytomegalovirus (HCMV) glycoprotein US9 downregulates the activating immune ligand MICA*008 to avoid NK cell activation, but the underlying mechanism remains unclear. Here, we show that the N-terminal signal peptide is the major US9 functional domain targeting MICA*008 to proteasomal degradation. The US9 signal peptide is cleaved with unusually slow kinetics and this transiently retained signal peptide arrests MICA*008 maturation in the endoplasmic reticulum (ER), and indirectly induces its degradation via the ER quality control system and the SEL1L-HRD1 complex. We further identify an accessory, signal peptide-independent US9 mechanism that directly binds MICA*008 and SEL1L. Collectively, we describe a dual-targeting immunoevasin, demonstrating that signal peptides can function as protein-integral effector domains. Glycoprotein US9 of human cytomegalovirus downregulates the activating immune ligand MICA*008 to avoid NK cell activation. Here, Seidel et al. show that the signal peptide of US9 is cleaved unusually slowly, causing MICA*008 to be retained in the endoplasmic reticulum (ER) and degraded via the ER quality control system.

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an \"alternative self\" mechanism for MHC class I inhibition.

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

Transgenic potato plants (Solanum tuberosum cv. Desiree) expressing the bacterial carbohydrate-binding module (CBM) family III, which is part of the Clostridium cellulovorans CBPA, under control of the CaMV 35S promoter were employed to investigate the influence of this protein on plant development. Eleven independent transgenic plants were found to express the cbm gene, at levels varying from one to four copies. Relative to non-transgenic controls, CBM-expressing plants were characterized by significantly more rapid elongation of the main stem. In addition, under both greenhouse and field conditions, the emergence rate of these plants was higher than in the controls, and their leaf area at early stages of development was larger, resulting in faster accumulation of fresh and dry weight than in control plants. Determination of cell size indicated that epidermal cells in young tissue were significantly larger in CBM-expressing than in control potato plants. These findings suggest that the CBM influence at the cellular level my cause significant alterations in plant growth both in tissue culture and in vivo under field conditions.

The past few years have witnessed a renaissance in the field of immuno-oncology largely due to the clinical success in targeting the immune checkpoints CTLA-4 and PD-1. Towards identification of novel immune checkpoint drug targets we developed a dedicated predictive discovery platform.The B7/CD28 discovery platform is a predictive model based on genomic and protein features along with expression patterns of known B7/CD28 proteins. The platform has been tested and validated extensively and has demonstrated its validity by identifying non-novel immune checkpoints such as TIGIT and VISTA, which were not used in the design stage.The B7/CD28 predictive platform was employed to identify several novel immune checkpoint candidates which are currently in different validation stages. In this poster, we will describe our discovery approach as well as our validation path. In addition, we will present experimental data demonstrating the immuno-modulatory function and expression patterns of several of our novel immune checkpoints. These experimental results serve as an additional confirmation to the accuracy of our B7/CD28 predictive discovery platform and shed light on the therapeutic potential of the novel immune checkpoints identified using this unique discovery approach.

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an “alternative self” mechanism for MHC class I inhibition.

Members of the B7/CD28 family of immune checkpoints, such as CTLA4, PD1 and PDL-1, play critical roles in T cell regulation, and have emerged as promising drug targets for cancer immunotherapy. We hypothesize that additional novel members of the B7/CD28 family play a role as negative immune regulators, and thus may serve as targets for therapeutic mAbs. Utilizing Compugen's predictive discovery platform, we identified eleven novel proteins that may serve as potential immune checkpoint candidates. The therapeutic potential of four of these proteins, CGEN-15001T, CGEN-15022, CGEN-15049 and CGEN-15052, was confirmed following validation of their immunomodulatory properties and demonstration of their expression in various cancers. Here we present results for two of these novel immune checkpoint candidates, CGEN-15049 and CGEN-15052.A recombinant protein consisting of the extracellular domain of CGEN-15049 fused to an IgG Fc domain was shown to inhibit T cell activation and enhance iTregs differentiation. Moreover, ectopically expressed CGEN-15049 inhibits activation of melanoma-specific CTLs and dampens function of NK cells, supporting a role for this protein in tumor immune modulation. IHC studies indicate that CGEN-15049 is expressed in the tumor cells and in the tumor infiltrating immune cells of multiple epithelial cancers.CGEN-15052 has demonstrated robust inhibition of T cell activation in several experimental settings, both as an ectopically expressed membrane protein and as an Fc fusion protein. IHC studies indicate that CGEN-15052 is expressed in multiple epithelial cancers, with particularly high expression in lung cancer samples.Taken together, the ability of both of these proteins to modulate immune response in several types of cells that play key roles in cancer immune evasion, and their tumor expression profile, indicate that CGEN-15049 and CGEN-15052 are potential immune checkpoints that may serve as targets for cancer immunotherapy.

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. NK cell activity is regulated by signals received from activating and inhibitory receptors. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically targets MICA*008 to proteasomal degradation, thus hindering the elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines. Human cytomegalovirus (HCMV) is a common pathogen that usually causes asymptomatic infection in the immunocompetent population, but the immunosuppressed and fetuses infected in utero suffer mortality and disability due to HCMV disease. Current HCMV treatments are limited and no vaccine has been approved, despite significant efforts. HCMV encodes many genes of unknown function, and virus-host interactions are only partially understood. Here, we discovered that a hitherto uncharacterized HCMV protein, UL147A, downregulates the expression of an activating immune ligand allele named MICA*008, thus hindering the elimination of HCMV-infected cells. Elucidating HCMV immune evasion mechanisms could aid in the development of novel HCMV treatments and vaccines. Furthermore, MICA*008 is a highly prevalent allele implicated in cancer immune evasion, autoimmunity and graft rejection. In this work we have shown that UL147A interferes with MICA*008’s poorly understood, nonstandard maturation pathway. Study of UL147A may enable manipulation of its expression as a therapeutic measure against HCMV.