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Updated: Mar 12, 2026
Simultaneous Imaging and Flow-Cytometry-based Detection of Multiple Fluorescent Senescence Markers in Therapy-Induced Senescent Cancer Cells
Published on: July 12, 2022
Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells
Fabrizio Antonangeli1, Alessandra Soriani2, Biancamaria Ricci1
1Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome , Rome, Italy.
Abstract:
Recognition of tumor cells by the immune system is a key step in cancer eradication. Melphalan is an alkylating agent routinely used in the treatment of patients with multiple myeloma (MM), but at therapeutic doses it leads to an immunosuppressive state due to lymphopenia. Here, we used a mouse model of MM to investigate the ability of in vivo treatment with low doses of melphalan to modulate natural killer (NK) cell activity, which have been shown to play a major role in the control of MM growth. Melphalan treatment was able to enhance the surface expression of the stress-induced NKG2D ligands RAE-1 and MULT-1, and of the DNAM-1 ligand PVR (CD155) on MM cells, leading to better tumor cell recognition and killing by NK cells, as highlighted by NK cell increased degranulation triggered by melphalan-treated tumor cells. Remarkably, NK cell population was not affected by the melphalan dose used, but rather displayed activation features as indicated by CD107a and CD69 expression. Furthermore, we showed that low doses of melphalan fail to induce tumor cell apoptosis, but promote the in vivo establishment of a senescent tumor cell population, harboring high levels of the stress-induced ligands RAE-1 and PVR. Taken together our data support the concept of using chemotherapy in order to boost antitumor innate immune responses and report the possibility to induce cellular senescence of tumor cells in vivo.
Insights
Low-dose melphalan chemotherapy enhances natural killer (NK) cell activity against multiple myeloma (MM) cells. This approach boosts anti-tumor immunity by inducing cellular senescence in tumor cells without affecting NK cell populations.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Natural killer (NK) cells are crucial for eradicating cancer cells.
- Melphalan, an alkylating agent, treats multiple myeloma (MM) but causes immunosuppression at therapeutic doses.
- Investigating low-dose melphalan's effect on NK cell activity in MM is important.
Purpose of the Study:
- To investigate the effect of low-dose melphalan on NK cell activity in a mouse model of MM.
- To determine if low-dose melphalan can enhance anti-tumor immune responses.
- To explore the induction of cellular senescence in MM cells by low-dose melphalan.
Main Methods:
- Used a mouse model of multiple myeloma (MM).
- Administered low doses of melphalan *in vivo*.
- Analyzed NK cell activity, NKG2D and DNAM-1 ligand expression on MM cells, and tumor cell apoptosis/senescence.
Main Results:
- Low-dose melphalan enhanced expression of NKG2D ligands (RAE-1, MULT-1) and DNAM-1 ligand (PVR) on MM cells.
- Melphalan-treated MM cells showed increased recognition and killing by NK cells, evidenced by enhanced degranulation.
- NK cell populations remained unaffected, but displayed activation markers (CD107a, CD69).
- Low-dose melphalan induced cellular senescence in MM cells, not apoptosis, with elevated stress-induced ligands.
Conclusions:
- Low-dose melphalan can boost anti-tumor innate immune responses by enhancing NK cell activity.
- This chemotherapy strategy can induce *in vivo* cellular senescence in tumor cells.
- Combining chemotherapy with immunotherapy warrants further investigation for MM treatment.
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