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Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

APC:

allophycocyanin

CFSE:

carboxyfluorescein diacetate succinimidyl ester

IgSF:

immunoglobulin superfamily

LEAF:

low endotoxin, azide-free

MDA:

MDA-MB-453

NKG2D:

Natural Killer Group 2D

NKp30:

NK p30 receptor

NKp46:

NK p46 receptor

PBMCs:

peripheral blood mononuclear cells

PI:

propidium iodide

PVR:

poliovirus receptor

SEM:

standard error of measurement

TIGIT:

T cell Ig and ITIM domain

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Acknowledgements

This work is partly supported by American Cancer Society Institutional Research Grant Number 57-001-53 and Cancer League of Colorado 163479.

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Authors and Affiliations

  1. Department of Surgery, University of Colorado Anschutz Medical Campus, RC1-North Building, P18-8116, Aurora, CO, 80045, USA

    Feng Xu, Alexander Sunderland, Yue Zhou, Richard D. Schulick, Barish H. Edil & Yuwen Zhu

  2. Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang, 110004, Liaoning, China

    Feng Xu

  3. Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, 310027, China

    Yue Zhou

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  1. Feng Xu
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  2. Alexander Sunderland
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Correspondence to Yuwen Zhu.

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Xu, F., Sunderland, A., Zhou, Y. et al. Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. Cancer Immunol Immunother 66, 1367–1375 (2017). https://doi.org/10.1007/s00262-017-2031-x

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  • DOI: https://doi.org/10.1007/s00262-017-2031-x

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