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

Autor: Christian H. Wetzel, Hartmut Goldschmidt, Vladimir M. Milenkovic, Mark Berneburg, Mathias Witzens-Harig, György Vereb, Ayse Nur Menevse, Arpad Szoor, Michael Boutros, Antonio Sorrentino, Chih-Yeh Chen, Anchana Rathinasamy, Philipp Beckhove, Sebastian Haferkamp, Klaus G. Griewank, Martin Ehrenschwender, Gertrud Knoll, Tillmann Michels, Madlen Ditz, Valentina Volpin, Anja Seckinger, Dirk Hose, Nisit Khandelwal
Přispěvatelé: Hematology, Basic (bio-) Medical Sciences
Rok vydání: 2020
Předmět:
0301 basic medicine
endocrine system
Cancer Research
Calcium-Calmodulin-Dependent Protein Kinase Type 1/biosynthesis
medicine.medical_treatment
Immunology
B7-H1 Antigen/antagonists & inhibitors
Medizin
Dermatology
Drug resistance
B7-H1 Antigen
Mice
03 medical and health sciences
Multiple Myeloma/immunology
0302 clinical medicine
Cancer immunotherapy
Neoplasms
Neoplasms/immunology
medicine
Animals
Humans
Multiple myeloma
hematology
business.industry
Melanoma
Cancer
T-Lymphocytes
Cytotoxic/immunology
medicine.disease
Immune checkpoint
CTL
030104 developmental biology
Calcium-Calmodulin-Dependent Protein Kinase Type 1
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
oncology
Immunotherapy/methods
Cancer research
Immunotherapy
Multiple Myeloma
business
T-Lymphocytes
Cytotoxic
Genetic screen
Zdroj: Cancer Immunology Research. 8:1163-1179
ISSN: 2326-6074
2326-6066
Popis: 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.
Databáze: OpenAIRE
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