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Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis
- Source :
- Journal for ImmunoTherapy of Cancer, Vol 9, Iss 4 (2021), Journal for Immunotherapy of Cancer
- Publication Year :
- 2021
- Publisher :
- BMJ Publishing Group, 2021.
-
Abstract
- Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Emerging data suggest that CLL-cells efficiently evade immunosurveillance. T-cell deficiencies in CLL include immuno(metabolic) exhaustion that is achieved by inhibitory molecules, with programmed cell death 1/programmed cell death ligand 1 (PD-L1) signaling emerging as a major underlying mechanism. Moreover, CLL-cells are characterized by a close and recurrent interaction with their stromal niches in the bone marrow and lymph nodes. Here, they receive nurturing signals within a well-protected environment. We could previously show that the interaction of CLL-cells with stroma leads to c-Myc activation that is followed by metabolic adaptations. Recent data indicate that c-Myc also controls expression of the immune checkpoint molecule PD-L1. Therefore, we sought out to determine the role of stromal contact for the CLL-cells’ PD-L1 expression and thus their immuno-evasive phenotype.To do so, we analyzed PD-L1 expression on CLL cell (subsets) in untreated patients and on healthy donor-derived B-cells. Impact of stromal contact on PD-L1 expression on CLL-cells and the underlying signaling pathways were assessed in well-established in vitro niche models. Ex vivo and in vitro findings were validated in the Eµ-TCL1 transgenic CLL mouse model.We found increased PD-L1 expression on CLL-cells as compared with B-cells that was further enhanced in a cell-to-cell contact-dependent manner by stromal cells. In fact, circulating recent stromal-niche emigrants displayed higher PD-L1 levels than long-time circulating CLL-cells. Using our in vitro niche model, we show that a novel Notch-c-Myc-enhancer of zeste homolog 2 (EZH2) signaling axis controls PD-L1 upregulation. Ultimately, elevated PD-L1 levels conferred increased resistance towards activated autologous T-cells.In summary, our findings support the notion that the CLL microenvironment contributes to immune escape variants. In addition, several targetable molecules (eg, Notch or EZH2) could be exploited in view of improving immune responses in patients with CLL, which warrants further in-depth investigation.
- Subjects :
- Cancer Research
Chronic lymphocytic leukemia
T-Lymphocytes
immunomodulation
Lymphocyte Activation
B7-H1 Antigen
hemic and lymphatic diseases
Tumor Cells, Cultured
Tumor Microenvironment
Immunology and Allergy
hematologic neoplasms
RC254-282
Clinical/Translational Cancer Immunotherapy
Receptors, Notch
Gene Expression Regulation, Leukemic
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunosurveillance
Leukemia
Oncology
Molecular Medicine
Signal transduction
Signal Transduction
Stromal cell
Immunology
Mice, Transgenic
Biology
programmed cell death 1 receptor
Cell Line
Proto-Oncogene Proteins c-myc
Downregulation and upregulation
Paracrine Communication
medicine
B-lymphocytes
tumor microenvironment
Animals
Humans
Enhancer of Zeste Homolog 2 Protein
Pharmacology
Tumor microenvironment
medicine.disease
Leukemia, Lymphocytic, Chronic, B-Cell
Immune checkpoint
Coculture Techniques
Mice, Inbred C57BL
Case-Control Studies
Cancer research
Tumor Escape
Stromal Cells
Subjects
Details
- Language :
- English
- ISSN :
- 20511426
- Volume :
- 9
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal for ImmunoTherapy of Cancer
- Accession number :
- edsair.doi.dedup.....5fd35b50fedbdc830b49291192a2c104