<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack"^^ . "Cancer is one of the leading causes of mortality worldwide. An important hallmark of\r\ncancer is its ability to escape immune surveillance by developing several\r\nimmunological obstacles. These include a plethora of mechanisms that either dampen\r\nimmune cell functionality, or foster tumor cell resistance towards immune attack.\r\nImmunotherapeutic strategies, such as immune checkpoint blockade, have emerged\r\nas promising therapeutic approaches for cancer treatment. However the majority of\r\ntumor patients are refractory to current immune therapeutic tools, emphasizing the\r\nneed to identify more key players that could radically improve immunotherapy.\r\nThis study aimed to systematically identify novel tumor-associated immune modulators\r\nby performing a high-throughput RNAi screen and subsequently validate novel\r\ncandidate genes whose blockade could potentially enhance anti-tumor immune\r\nresponse in tumor patients. Starting from a pancreatic ductal adenocarcinoma (PDAC)\r\nco-culture model, 2514 genes were knocked down in a luciferase-expressing tumor\r\ncell line using a siRNA library. Subsequently, the transfected tumor cells were cocultured\r\nwith HLA-A2.1+- matched tumor infiltrating lymphocytes (TILs). TIL-mediated\r\ncytotoxicity was then assessed by measuring the remaining luciferase intensity of\r\ntransfected tumor cells. In order to exclude genes whose knock-down affected cell\r\nviability per se, we cultivated tumor cells with the siRNA library in the absence of TILs.\r\nThe primary screening revealed 155 potential candidate genes (hits) whose\r\ndownregulation increased T cell-mediated tumor lysis more efficiently than PD-L1\r\nknockdown. The hit-list generated in the primary screen was narrowed down to 108\r\nhits after performing a secondary screen. Among these candidate genes, salt-inducible\r\nkinase 3 (SIK3) was selected for extensive validation analysis, as this protein kinase\r\nis overexpressed in tumor biopsies and its role in immune escape mechanisms has\r\nnot been reported so far. SIK3 impairment in tumor cells enhanced T cell mediated\r\nkilling in several co-culture models derived from different cancer entities. We showed\r\nthat SIK3 sustained intrinsic tumor resistance to immune cell attack, rather than\r\nmodulating T cell functionality. We observed that T cells expressed TNF-α upon coculture\r\nwith tumor cells, and that this cytokine elicited tumor cell growth in SIK3-\r\nproficinent cells. On the contrary, SIK3 depletion sensitized tumor cells towards TNFPage\r\nVIII\r\nα-induced apoptosis by regulating NF-κB activation via HDAC4. To prove the\r\ntranslational relevance of SIK3 blockade for cancer immunotherapy, we used a small\r\nmolecule compound which recapitulated the effect of SIK3 genetic depletion.\r\nAdditionally, stable knockdown of SIK3 in tumor cells resulted in retardation of tumor\r\ngrowth after adoptive cell transfer of TILs in a xenograft mouse model.\r\nThis study describes a robust method for a comprehensive identification of novel\r\nimmune modulators in solid tumors. Furthermore, this work provides the rationale of\r\nSIK3 inhibition as a novel therapeutic strategy for cancer treatment."^^ . "2021" . . . . . . . "Antonio"^^ . "Sorrentino"^^ . "Antonio Sorrentino"^^ . . . . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (PDF)"^^ . . . "PhD Thesis AS.pdf"^^ . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (Other)"^^ . . . . . . "preview.jpg"^^ . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (Other)"^^ . . . . . . "medium.jpg"^^ . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (Other)"^^ . . . . . . "small.jpg"^^ . . . "A screening for novel immune modulators identifies\r\nSIK3 kinase as a regulator of tumor resistance to\r\nT cell attack (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #23273 \n\nA screening for novel immune modulators identifies \nSIK3 kinase as a regulator of tumor resistance to \nT cell attack\n\n" . "text/html" . .