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Updated: Feb 28, 2026
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions
Feng Xu1,2, Alexander Sunderland1, Yue Zhou1,3
1Department of Surgery, University of Colorado Anschutz Medical Campus, RC1-North Building, P18-8116, Aurora, CO, 80045, USA.
Abstract:
Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity. More importantly, TIGIT is upregulated upon NK cell activation via ADCC. Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. Thus, our findings suggest that PVR-like receptors regulate NK cell functions and can be targeted for improving trastuzumab therapy for breast cancer.
Insights
Targeting PVR-like receptors, like TIGIT, can enhance trastuzumab therapy for Her2-positive breast cancer. Blocking these receptors boosts NK cell activity against resistant tumors.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Trastuzumab is a first-line therapy for Her2-positive breast cancer.
- Resistance to trastuzumab, often due to impaired NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), limits treatment efficacy.
- Poliovirus receptor (PVR)-like molecules are implicated in lymphocyte function.
Purpose of the Study:
- To investigate the role of PVR-like receptors in NK cell-mediated ADCC against breast cancer.
- To explore the potential of targeting PVR-like receptors to overcome trastuzumab resistance.
Main Methods:
- Analysis of PVR-like receptor expression on human NK cells.
- Investigation of TIGIT expression on specific NK cell subsets (CD16+).
- Assessment of NK cell activity upon blockade of PVR-like receptors and their ligands during trastuzumab treatment.
Main Results:
- All PVR-like receptors are expressed on human NK cells; TIGIT is enriched on CD16+ NK cells.
- TIGIT expression increases on NK cells activated via ADCC.
- Blocking TIGIT or CD112R enhances trastuzumab-induced antitumor responses mediated by human NK cells.
Conclusions:
- PVR-like receptors, particularly TIGIT, modulate NK cell function in the context of trastuzumab therapy.
- Targeting PVR-like receptors offers a promising strategy to improve trastuzumab efficacy in Her2-positive breast cancer.
- Disrupting PVR-like receptor-ligand interactions can enhance NK cell-mediated antitumor immunity.
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