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PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity

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收录情况： ◇ SCIE

作者：
Du Ruoxin[1,2] * ; Zhang Xiangmei[2,3] * ; Lu Xiyan[4] ; Ma Xiangmin[5,8] ; Guo Xinyan[1] ; Shi Chao[2,6] ; Ren Xiaofei[2,6] ; Ma Xindi[2,6] ; He Yutong[7] ; Gao Yuan[1,*1] ; Liu Yunjiang[2,6,*2] ;
机构： [1]State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China [2]Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Hebei Medical University, Shijiazhuang City 050017, China [3]Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang City 050011, China [4]Outpatient Department of the Second Affiliated Hospital of the Fourth Military Medical University, Xi’an 710032, China [5]Department of Breast Surgery, Handan Central Hospital, Handan City 056000, China [6]Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang City 050011, China [7]Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang City 050011, China [8]Research Centre, The Fourth Hospital of Hebei Medical University, China
出处：
DOI： 10.1016/j.drup.2023.100947
ISSN：

摘要：
Trastuzumab is a humanized monoclonal antibody, and has been clinical employed to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, drug resistance to trastuzumab remains a challenge due to the generally uncharacterized interactive immune responses within the tumor tissue. In this study, by means of single-cell sequencing, we identified a novel podoplanin-positive (PDPN+) cancer-associated fibroblasts (CAFs) subset, which was enriched in trastuzumab resistant tumor tissues. Furthermore, we found that PDPN+ CAFs promote resistance to trastuzumab in HER2+ breast cancer by secreting immunosuppressive factors indoleamine 2,3-dioxygenase 1 (IDO1) as well as tryptophan 2,3-dioxygenase 2 (TDO2), thereby suppressing antibody-dependent cell-mediated cytotoxicity (ADCC), which was mediated by functional NK cells. A dual inhibitor IDO/TDO-IN-3 simultaneously targeting IDO1 and TDO2 showed a promising effect on reversing PDPN+ CAFs-induced suppression of NK cells mediated ADCC. Collectively, a novel subset of PDPN+ CAFs was identified in this study, which induced trastuzumab resistance in breast cancer of HER2+ status via inhibiting ADCC immune response mediated by NK cells, hinting that PDPN+ CAFs could be a novel target of treatment to increase the sensitivity of HER2+ breast cancer to trastuzumab.Copyright © 2023. Published by Elsevier Ltd.

基金：
This study was supported by grants from the Natural Science Foundation of Hebei Province, China (No. H2020206210); Project of "100 Foreign Experts Plan of Hebei Province", China (No. 2022001); National Natural Science Foundation of China-General Program (81902678); Hong Kong Scholars Program and the Young Elite Scientist Sponsorship Program by CAST (YESS20210177).
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外文
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出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 药学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 药学
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出版当年[2023]版：
Q1 PHARMACOLOGY & PHARMACY
最新[2023]版：
Q1 PHARMACOLOGY & PHARMACY

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China [2]Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Hebei Medical University, Shijiazhuang City 050017, China
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China [2]Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Hebei Medical University, Shijiazhuang City 050017, China [6]Department of Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang City 050011, China [*1]169 Changle West Road, Xi’an 710032, China [*2]12 Jiankang Road, Shijiazhuang City 050011, China.
推荐引用方式(GB/T 7714)：
Du Ruoxin,Zhang Xiangmei,Lu Xiyan,et al.PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity[J].DRUG RESISTANCE UPDATES.2023,68:doi:10.1016/j.drup.2023.100947.
APA：
Du Ruoxin,Zhang Xiangmei,Lu Xiyan,Ma Xiangmin,Guo Xinyan...&Liu Yunjiang.(2023).PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity.DRUG RESISTANCE UPDATES,68,
MLA：
Du Ruoxin,et al."PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity".DRUG RESISTANCE UPDATES 68.(2023)

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