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primary topic: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma

A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma
type: Article
abstract: Despite tremendous progresses in cancer immunotherapy, a plethora of tumor patients is still refractory to current immunotherapeutic strategies. Unresponsiveness to therapy is ascribed to the ability of cancer cells to elude the immunosurveillance. Indeed, by taking advantage of different immune-checkpoint molecules tumor cells can either dampen immune cell functionality or promote tumor cell resistance towards immune attack. The current study aimed at identifying novel tumor-associated immune-checkpoint molecules by developing a RNAi high-throughput (HTP) screening and successively corroborate candidate genes whose blockade increases anti-tumor immune response. Hence, I generated stable luciferase expressing multiple myeloma cells, transfected them with a siRNA library targeting 2887 genes (enriched for kinases and surface-associated molecules) and co-cultured them with HLA-A2-matched patient-derived marrow-infiltrating lymphocytes (MILs). T cell-mediated killing of tumor cells was assessed by measuring the remaining luciferase activity of knocked down tumor cells. The HTP screening revealed 128 genes whose knockdown increased T cell-mediated tumor cell death more efficiently than the positive control CCR9. To validate the results, candidate genes were re-tested in a secondary screening that allowed to distinguish between genes altering tumor susceptibility towards MIL-mediated killing and those impairing MIL activity. Among the candidate immune-checkpoints the serine/threonine protein kinase CAMK1D was selected for extensive validation. Knockdown of CAMK1D resulted in increased tumor susceptibility towards MIL-mediated killing. In particular, CAMK1D was shown to support intrinsic tumor resistance towards T cell attack by interfering with the apoptotic signaling cascade. By directly interacting with effector caspases, CAMK1D inhibits caspases activation and activity via phosphorylation. In line, CAMK1D depletion sensitizes tumor cells to FasLinduced apoptosis by MI…
date: 2023
author list: authors
type: EPrint
type: DoctoralThesisEPrint
is part of: repository
has document: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
has document: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)

A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
type: Document
has file: Dissertation_Valentina_Volpin_2018.pdf
has part: Dissertation_Valentina_Volpin_2018.pdf

Valentina Volpin
type: Person
given name: Valentina
family name: Volpin

A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)
type: Document
is version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
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A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)
type: Document
is version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
is volatile version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
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A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)
type: Document
is version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
is volatile version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
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A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)
type: Document
is version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
is volatile version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
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A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (Other)
type: Document
is version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
is volatile version of: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma (PDF)
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primary topic: A screening for novel immune-checkpoints identifies CAMK1D as a kinase responsible for immune resistance in multiple myeloma