2. Academic Validation
  3. CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti-PD-L1 Treatment

CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti-PD-L1 Treatment

  • Cancer Immunol Res. 2020 Sep;8(9):1163-1179. doi: 10.1158/2326-6066.CIR-19-0608.
Valentina Volpin 1 2,  Tillmann Michels 1 2 3,  Antonio Sorrentino 1 2,  Ayse N Menevse 1,  Gertrud Knoll 4,  Madlen Ditz 1,  Vladimir M Milenkovic 5,  Chih-Yeh Chen 1,  Anchana Rathinasamy 1,  Klaus Griewank 6,  Michael Boutros 7,  Sebastian Haferkamp 8,  Mark Berneburg 8,  Christian H Wetzel 5,  Anja Seckinger 9,  Dirk Hose 10,  Hartmut Goldschmidt 11,  Martin Ehrenschwender 4,  Mathias Witzens-Harig 12,  Arpad Szoor 13,  Gyorgy Vereb 13,  Nisit Khandelwal 3,  Philipp Beckhove 14 2 15
Affiliations

Affiliations

  • 1 Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
  • 2 German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
  • 3 iOmx Therapeutics AG, Martinsried/Munich, Germany.
  • 4 Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany.
  • 5 Department of Psychiatry and Psychotherapy, Molecular Neurosciences, University of Regensburg, Regensburg, Germany.
  • 6 Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium, Essen, Germany.
  • 7 German Cancer Research Center (DKFZ), Division Signalling and Functional Genomics, Heidelberg, Germany.
  • 8 Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
  • 9 Labor für Myelomforschung, Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
  • 10 Department of Hematology and Immunology, Myeloma Center Brussels, Jette, Belgium.
  • 11 Department of Internal Medicine V and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
  • 12 Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
  • 13 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 14 Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany. [email protected].
  • 15 Department of Hematology, Oncology, Internal Medicine 3, University Hospital Regensburg, Regensburg, Germany.
PMID: 32665263 DOI: 10.1158/2326-6066.CIR-19-0608
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 by CAMK1D expressed in anti-PD-L1-refractory tumors via T-cell recognition may have contributed to tumor immune resistance.

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