<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma"^^ . "Despite tremendous progresses in cancer immunotherapy, a plethora of tumor patients\r\nis still refractory to current immunotherapeutic strategies. Unresponsiveness to therapy is\r\nascribed to the ability of cancer cells to elude the immunosurveillance. Indeed, by taking\r\nadvantage of different immune-checkpoint molecules tumor cells can either dampen immune\r\ncell functionality or promote tumor cell resistance towards immune attack.\r\nThe current study aimed at identifying novel tumor-associated immune-checkpoint molecules\r\nby developing a RNAi high-throughput (HTP) screening and successively corroborate\r\ncandidate genes whose blockade increases anti-tumor immune response.\r\nHence, I generated stable luciferase expressing multiple myeloma cells, transfected them with\r\na siRNA library targeting 2887 genes (enriched for kinases and surface-associated molecules)\r\nand co-cultured them with HLA-A2-matched patient-derived marrow-infiltrating\r\nlymphocytes (MILs). T cell-mediated killing of tumor cells was assessed by measuring the\r\nremaining luciferase activity of knocked down tumor cells. The HTP screening revealed 128\r\ngenes whose knockdown increased T cell-mediated tumor cell death more efficiently than the\r\npositive control CCR9.\r\nTo validate the results, candidate genes were re-tested in a secondary screening that allowed\r\nto distinguish between genes altering tumor susceptibility towards MIL-mediated killing and\r\nthose impairing MIL activity.\r\nAmong the candidate immune-checkpoints the serine/threonine protein kinase CAMK1D was\r\nselected for extensive validation. Knockdown of CAMK1D resulted in increased tumor\r\nsusceptibility towards MIL-mediated killing. In particular, CAMK1D was shown to support\r\nintrinsic tumor resistance towards T cell attack by interfering with the apoptotic signaling\r\ncascade. By directly interacting with effector caspases, CAMK1D inhibits caspases activation\r\nand activity via phosphorylation. In line, CAMK1D depletion sensitizes tumor cells to FasLinduced\r\napoptosis by MILs. These results obtained in the hematological malignancy were\r\nfurther confirmed in uveal melanoma emphasizing the relevant role of CAMK1D in different\r\ntumor entities.\r\nTaken together, this study describes the establishment of a HTP-discovery platform to\r\nunravel the arsenal of immune-checkpoint molecules used by cancer cells to escape the\r\nimmune system. The molecular pathway of CAMK1D is described highlighting the\r\nimportance of discovering immune-checkpoints that mediate resistance towards T cell attack."^^ . "2023" . . . . . . . "Valentina"^^ . "Volpin"^^ . "Valentina Volpin"^^ . . . . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (PDF)"^^ . . . "Dissertation_Valentina_Volpin_2018.pdf"^^ . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (Other)"^^ . . . . . . "preview.jpg"^^ . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (Other)"^^ . . . . . . "medium.jpg"^^ . . . "A screening for novel immune-checkpoints\r\nidentifies CAMK1D as a kinase responsible\r\nfor immune resistance in multiple myeloma (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #24715 \n\nA screening for novel immune-checkpoints \nidentifies CAMK1D as a kinase responsible \nfor immune resistance in multiple myeloma\n\n" . "text/html" . .