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 |
Externí odkaz: |