Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions

Xuejun Fan; Zihao Yuan; Yueshui Zhao; Wei Xiong; Hao-Ching Hsiao; Rahmawati Pare; Jianmin Ding; Ahmad Almosa; Kai Sun; Songlin Zhang; Robert E. Jordan; Cheok Song Lee; Zhiqiang An; Ningyan Zhang

doi:10.1038/s42003-022-03931-7

Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions

Xuejun Fan, Zihao Yuan, Yueshui Zhao, Wei Xiong, Hao-Ching Hsiao, Rahmawati Pare, Jianmin Ding, Ahmad Almosa, Kai Sun, Songlin Zhang, Robert E. Jordan, Cheok Song Lee, Zhiqiang An, Ningyan Zhang

Western Sydney University

Research output: Contribution to journal › Article › peer-review

Abstract

Natural killer (NK) cells mediate antibody dependent cytotoxic killing of cancer cells via cross-linking FcγR on NK cells with IgG-Fc. Studies have shown that the single-hinge cleaved IgGs (scIgGs) have dysfunctional Fc and failed engagement with FcγRs on immune cells. However, little is known about how scIgGs impact on antitumor immunity in the tumor microenvironment. In this study, we revealed a significant association of tumor scIgGs with tumor progression and poor outcomes of breast cancer patients (n = 547). Using multiple mouse tumor models, we demonstrated that tumor scIgGs reduced NK cell cytotoxic activities and resulted in aggressive tumor progression. We further showed that an anti-hinge specific monoclonal antibody (AHA) rescued the dysfunctional Fc in scIgGs by providing a functional Fc and restored NK cell cytotoxic activity. These findings point to a novel immunotherapeutic strategy to enhance Fc engagement with FcγRs for activation of anticancer immunity.

Original language	English
Article number	960
Number of pages	14
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03931-7
Publication status	Published - 2022

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Â© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.

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title = "Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions",

abstract = "Natural killer (NK) cells mediate antibody dependent cytotoxic killing of cancer cells via cross-linking FcγR on NK cells with IgG-Fc. Studies have shown that the single-hinge cleaved IgGs (scIgGs) have dysfunctional Fc and failed engagement with FcγRs on immune cells. However, little is known about how scIgGs impact on antitumor immunity in the tumor microenvironment. In this study, we revealed a significant association of tumor scIgGs with tumor progression and poor outcomes of breast cancer patients (n = 547). Using multiple mouse tumor models, we demonstrated that tumor scIgGs reduced NK cell cytotoxic activities and resulted in aggressive tumor progression. We further showed that an anti-hinge specific monoclonal antibody (AHA) rescued the dysfunctional Fc in scIgGs by providing a functional Fc and restored NK cell cytotoxic activity. These findings point to a novel immunotherapeutic strategy to enhance Fc engagement with FcγRs for activation of anticancer immunity.",

author = "Xuejun Fan and Zihao Yuan and Yueshui Zhao and Wei Xiong and Hao-Ching Hsiao and Rahmawati Pare and Jianmin Ding and Ahmad Almosa and Kai Sun and Songlin Zhang and Jordan, {Robert E.} and Lee, {Cheok Song} and Zhiqiang An and Ningyan Zhang",

year = "2022",

doi = "10.1038/s42003-022-03931-7",

language = "English",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

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TY - JOUR

T1 - Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions

AU - Fan, Xuejun

AU - Yuan, Zihao

AU - Zhao, Yueshui

AU - Xiong, Wei

AU - Hsiao, Hao-Ching

AU - Pare, Rahmawati

AU - Ding, Jianmin

AU - Almosa, Ahmad

AU - Sun, Kai

AU - Zhang, Songlin

AU - Jordan, Robert E.

AU - Lee, Cheok Song

AU - An, Zhiqiang

AU - Zhang, Ningyan

PY - 2022

Y1 - 2022

N2 - Natural killer (NK) cells mediate antibody dependent cytotoxic killing of cancer cells via cross-linking FcγR on NK cells with IgG-Fc. Studies have shown that the single-hinge cleaved IgGs (scIgGs) have dysfunctional Fc and failed engagement with FcγRs on immune cells. However, little is known about how scIgGs impact on antitumor immunity in the tumor microenvironment. In this study, we revealed a significant association of tumor scIgGs with tumor progression and poor outcomes of breast cancer patients (n = 547). Using multiple mouse tumor models, we demonstrated that tumor scIgGs reduced NK cell cytotoxic activities and resulted in aggressive tumor progression. We further showed that an anti-hinge specific monoclonal antibody (AHA) rescued the dysfunctional Fc in scIgGs by providing a functional Fc and restored NK cell cytotoxic activity. These findings point to a novel immunotherapeutic strategy to enhance Fc engagement with FcγRs for activation of anticancer immunity.

AB - Natural killer (NK) cells mediate antibody dependent cytotoxic killing of cancer cells via cross-linking FcγR on NK cells with IgG-Fc. Studies have shown that the single-hinge cleaved IgGs (scIgGs) have dysfunctional Fc and failed engagement with FcγRs on immune cells. However, little is known about how scIgGs impact on antitumor immunity in the tumor microenvironment. In this study, we revealed a significant association of tumor scIgGs with tumor progression and poor outcomes of breast cancer patients (n = 547). Using multiple mouse tumor models, we demonstrated that tumor scIgGs reduced NK cell cytotoxic activities and resulted in aggressive tumor progression. We further showed that an anti-hinge specific monoclonal antibody (AHA) rescued the dysfunctional Fc in scIgGs by providing a functional Fc and restored NK cell cytotoxic activity. These findings point to a novel immunotherapeutic strategy to enhance Fc engagement with FcγRs for activation of anticancer immunity.

UR - http://hdl.handle.net/1959.7/uws:69866

U2 - 10.1038/s42003-022-03931-7

DO - 10.1038/s42003-022-03931-7

M3 - Article

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 960

ER -

Impairment of IgG Fc functions promotes tumor progression and suppresses NK cell antitumor actions

Abstract

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