Volpin, Valentina and Michels, Tillmann and Sorrentino, Antonio and Menevse, Ayse N. and Knoll, Gertrud and Ditz, Madlen and Milenkovic, Vladimir M. and Chen, Chih-Yeh and Rathinasamy, Anchana and Griewank, Klaus and Boutros, Michael and Haferkamp, Sebastian and Berneburg, Mark and Wetzel, Christian H. and Seckinger, Anja and Hose, Dirk and Goldschmidt, Hartmut and Ehrenschwender, Martin and Witzens-Harig, Mathias and Szoor, Arpad and Vereb, Gyorgy and Khandelwal, Nisit and Beckhove, Philipp (2020) CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti-PD-L1 Treatment. CANCER IMMUNOLOGY RESEARCH, 8 (9). pp. 1163-1179. ISSN 2326-6066, 2326-6074
Full text not available from this repository. (Request a copy)Abstract
The success of cancer immunotherapy is limited by resistance to immune checkpoint blockade. We therefore conducted a genetic screen to identify genes that mediated resistance against CTLs in anti-PD-L1 treatment-refractory human tumors. Using PD-L1-positive multiple myeloma cells cocultured with tumor-reactive bone marrow-infiltrating CTL as a model, we identified calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key modulator of tumor-intrinsic immune resistance. CAMK1D was coexpressed with PD-L1 in anti-PD-L1/PD-1 treatment-refractory cancer types and correlated with poor prognosis in these tumors. CAMK1D was activated by CTL through Fas-receptor stimulation, which led to CAMK1D binding to and phosphorylating caspase-3, -6, and -7, inhibiting their activation and function. Consistently, CAMK1D mediated immune resistance of murine colorectal cancer cells in vivo. The pharmacologic inhibition of CAMK1D, on the other hand, restored the sensitivity toward Fas-ligand treatment in multiple myeloma and uveal melanoma cells in vitro. Thus, rapid inhibition of the terminal apoptotic cascade byCAMK1D-expressed in anti-PD-L1-refractory tumors via T-cell recognition may have contributed to tumor immune resistance.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MULTIPLE-MYELOMA; BONE-MARROW; INFILTRATING LYMPHOCYTES; FAS LIGAND; STEM-CELL; EXPRESSION; CANCER; ANTIBODY; KINASE; PD-1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Medicine > Lehrstuhl für Psychiatrie und Psychotherapie Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2021 14:37 |
| Last Modified: | 15 Mar 2021 14:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43931 |
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