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Updated: Jul 23, 2025
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
AATF/Che-1 RNA polymerase II binding protein overexpression reduces the anti-tumor NK-cell cytotoxicity through
Matteo Caforio1, Nicola Tumino2, Cristina Sorino3
1Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
Introduction:
AATF/Che-1 over-expression in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated.
Methods:
Starting from ChIP-sequencing data we confirmed Che-1 enrichment on Nectin-1 promoter. Several co-cultures experiments between NK-cells and tumor cells transduced by lentiviral vectors carrying Che-1-interfering sequence, analyzed by flow-cytometry have allowed a detailed characterization of NK receptors and tumor ligands expression.
Results:
Here, we show that Che-1 is able to modulate the expression of Nectin-1 ligand at the transcriptional level, leading to the impairment of killing activity of NK-cells. Nectin-1 down-modulation induces a modification in NK-cell ligands expression able to interact with activating receptors and to stimulate NK-cell function. In addition, NK-cells from Che-1 transgenic mice, confirming a reduced expression of activating receptors, exhibit impaired activation and a preferential immature status.
Discussion:
The critical equilibrium between NK-cell ligand expression on tumor cells and the interaction with NK cell receptors is affected by Che-1 over-expression and partially restored by Che-1 interference. The evidence of a new role for Che-1 as regulator of anti-tumor immunity supports the necessity to develop approaches able to target this molecule which shows a dual tumorigenic function as cancer promoter and immune response modulator.
Insights
The transcription factor Che-1 (AATF) over-expression in tumors impairs NK-cell anti-tumor immunity by down-regulating Nectin-1, affecting cancer cell recognition and killing. Targeting Che-1 may restore immune function against tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- AATF/Che-1 is over-expressed in tumors, influencing proliferation and viability.
- Its impact on the anti-tumor immune response remains largely uninvestigated.
Purpose of the Study:
- To investigate the role of Che-1 in modulating the anti-tumor immune response.
- To determine how Che-1 affects Natural Killer (NK) cell activity in the context of solid tumors.
Main Methods:
- ChIP-sequencing to identify Che-1 binding sites.
- Co-culture experiments with NK cells and tumor cells with altered Che-1 expression.
- Flow cytometry to analyze NK cell receptors and tumor ligand expression.
Main Results:
- Che-1 modulates Nectin-1 ligand expression transcriptionally, impairing NK cell killing activity.
- Down-regulation of Nectin-1 by Che-1 alters NK cell ligand expression, affecting activation.
- NK cells from Che-1 transgenic mice show reduced activating receptor expression and impaired function.
Conclusions:
- Che-1 over-expression disrupts the balance between NK cell receptors and tumor ligands, hindering anti-tumor immunity.
- Che-1 acts as a regulator of anti-tumor immunity, with a dual role in cancer promotion and immune modulation.
- Targeting Che-1 is a potential therapeutic strategy to enhance anti-tumor immune responses.
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