Cover Image

CAMK1D triggers immune resistance of human tumor cells refractory to Anti-PD-L1 treatment

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 tum...

Full description

Saved in:
Bibliographic Details
Main Authors: Volpin, Valentina (Author) , Michels, Tillmann (Author) , Sorrentino, Antonio (Author) , Menevse, Ayse N. (Author) , Knoll, Gertrud (Author) , Ditz, Madlen (Author) , Milenkovic, Vladimir M. (Author) , Chen, Chih-Yeh (Author) , Rathinasamy, Anchana (Author) , Griewank, Klaus (Author) , Boutros, Michael (Author) , Haferkamp, Sebastian (Author) , Berneburg, Mark (Author) , Wetzel, Christian H. R. (Author) , Seckinger, Anja (Author) , Hose, Dirk (Author) , Goldschmidt, Hartmut (Author) , Ehrenschwender, Martin (Author) , Witzens-Harig, Mathias (Author) , Szoor, Arpad (Author) , Vereb, Gyorgy (Author) , Khandelwal, Nisit (Author) , Beckhove, Philipp (Author)
Format: Article (Journal)
Language:English
Published: July 14, 2020
In: Cancer immunology research
Year: 2020, Volume: 8, Issue: 9, Pages: 1163-1179
ISSN:2326-6074
DOI:10.1158/2326-6066.CIR-19-0608
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/2326-6066.CIR-19-0608
Verlag, lizenzpflichtig, Volltext: https://cancerimmunolres.aacrjournals.org/content/8/9/1163
Get full text
Author Notes:Valentina Volpin, Tillmann Michels, Antonio Sorrentino, Ayse N. Menevse, Gertrud Knoll, Madlen Ditz, Vladimir M. Milenkovic, Chih-Yeh Chen, Anchana Rathinasamy, Klaus Griewank, Michael Boutros, Sebastian Haferkamp, Mark Berneburg, Christian H. Wetzel, Anja Seckinger, Dirk Hose, Hartmut Goldschmidt, Martin Ehrenschwender, Mathias Witzens-Harig, Arpad Szoor, Gyorgy Vereb, Nisit Khandelwal, Philipp Beckhove
Description
Summary: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 by CAMK1D expressed in anti-PD-L1-refractory tumors via T-cell recognition may have contributed to tumor immune resistance.
Item Description:Gesehen am 02.02.2021
Physical Description:Online Resource
ISSN:2326-6074
DOI:10.1158/2326-6066.CIR-19-0608

Similar Items