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Updated: Sep 23, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
Blocking the PCNA/NKp44 Checkpoint to Stimulate NK Cell Responses to Multiple Myeloma
Muhammed Iraqi1, Avishay Edri1, Yariv Greenshpan1
1The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel.
Abstract:
Multiple Myeloma (MM) is a devastating malignancy that evades immune destruction using multiple mechanisms. The NKp44 receptor interacts with PCNA (Proliferating Cell Nuclear Antigen) and may inhibit NK cells' functions. Here we studied in vitro the expression and function of PCNA on MM cells. First, we show that PCNA is present on the cell membrane of five out of six MM cell lines, using novel anti-PCNA mAb developed to recognize membrane-associated PCNA. Next, we stained primary bone marrow (BM) mononuclear cells from MM patients and showed significant staining of membrane-associated PCNA in the fraction of CD38+CD138+ BM cells that contain the MM cells. Importantly, blocking of the membrane PCNA on MM cells enhanced the activity of NK cells, including IFN-γ-secretion and degranulation. Our results highlight the possible blocking of the NKp44-PCNA immune checkpoint by the mAb 14-25-9 antibody to enhance NK cell responses against MM, providing a novel treatment option.
Insights
Blocking Proliferating Cell Nuclear Antigen (PCNA) on multiple myeloma cells boosts natural killer (NK) cell activity. This discovery offers a promising new avenue for enhancing immune responses against this cancer.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Multiple Myeloma (MM) is a hematologic malignancy characterized by immune evasion.
- The NKp44 receptor is implicated in NK cell function and may interact with Proliferating Cell Nuclear Antigen (PCNA).
Purpose of the Study:
- To investigate the expression and function of membrane-associated PCNA on MM cells.
- To assess the impact of blocking membrane PCNA on NK cell activity against MM.
Main Methods:
- Utilized novel anti-PCNA monoclonal antibodies (mAbs) to detect membrane-associated PCNA on MM cell lines.
- Stained primary bone marrow mononuclear cells from MM patients.
- Assessed NK cell activity (IFN-γ secretion, degranulation) following PCNA blockade.
Main Results:
- PCNA was detected on the cell membrane of 5/6 MM cell lines.
- Significant membrane PCNA staining was observed on CD38+CD138+ cells in MM patient bone marrow.
- Blocking membrane PCNA enhanced NK cell effector functions, including IFN-γ secretion and degranulation.
Conclusions:
- Membrane-associated PCNA is a potential target on MM cells.
- Blocking the NKp44-PCNA interaction with mAb 14-25-9 can enhance NK cell-mediated anti-MM immunity.
- This represents a novel therapeutic strategy for Multiple Myeloma.
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