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

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 and Philipp Beckhove
Valentina Volpin
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
2German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
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Tillmann Michels
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
2German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
3iOmx Therapeutics AG, Martinsried/Munich, Germany.
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  • ORCID record for Tillmann Michels
Antonio Sorrentino
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
2German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
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Ayse N. Menevse
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
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Gertrud Knoll
4Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany.
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Madlen Ditz
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
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Vladimir M. Milenkovic
5Department of Psychiatry and Psychotherapy, Molecular Neurosciences, University of Regensburg, Regensburg, Germany.
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Chih-Yeh Chen
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
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Anchana Rathinasamy
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
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Klaus Griewank
6Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium, Essen, Germany.
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  • ORCID record for Klaus Griewank
Michael Boutros
7German Cancer Research Center (DKFZ), Division Signalling and Functional Genomics, Heidelberg, Germany.
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Sebastian Haferkamp
8Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
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Mark Berneburg
8Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
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Christian H. Wetzel
5Department of Psychiatry and Psychotherapy, Molecular Neurosciences, University of Regensburg, Regensburg, Germany.
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Anja Seckinger
9Labor für Myelomforschung, Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
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Dirk Hose
10Department of Hematology and Immunology, Myeloma Center Brussels, Jette, Belgium.
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Hartmut Goldschmidt
11Department of Internal Medicine V and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
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Martin Ehrenschwender
4Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany.
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Mathias Witzens-Harig
12Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
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Arpad Szoor
13Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Gyorgy Vereb
13Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Nisit Khandelwal
3iOmx Therapeutics AG, Martinsried/Munich, Germany.
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Philipp Beckhove
1Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany.
2German Cancer Research Center (DKFZ), Translational Immunology, Heidelberg, Germany.
14Department of Hematology, Oncology, Internal Medicine 3, University Hospital Regensburg, Regensburg, Germany.
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  • For correspondence: beckhove@rcii.de
DOI: 10.1158/2326-6066.CIR-19-0608 Published September 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1163–79

  • Received August 8, 2019.
  • Revision received March 16, 2020.
  • Accepted July 9, 2020.
  • Published first July 14, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (9)
September 2020
Volume 8, Issue 9
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CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti–PD-L1 Treatment
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 and Philipp Beckhove
Cancer Immunol Res September 1 2020 (8) (9) 1163-1179; DOI: 10.1158/2326-6066.CIR-19-0608

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CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti–PD-L1 Treatment
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 and Philipp Beckhove
Cancer Immunol Res September 1 2020 (8) (9) 1163-1179; DOI: 10.1158/2326-6066.CIR-19-0608
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