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CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer

BACKGROUND: There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome...

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Autores principales: Sun, Weilin, Wang, Xi, Wang, Daohan, Lu, Li, Lin, Hai, Zhang, Zhaoxiong, Jia, Yangpu, Nie, Xinyang, Liu, Tong, Fu, Weihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295658/
https://www.ncbi.nlm.nih.gov/pubmed/35851310
http://dx.doi.org/10.1136/jitc-2022-005063
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author Sun, Weilin
Wang, Xi
Wang, Daohan
Lu, Li
Lin, Hai
Zhang, Zhaoxiong
Jia, Yangpu
Nie, Xinyang
Liu, Tong
Fu, Weihua
author_facet Sun, Weilin
Wang, Xi
Wang, Daohan
Lu, Li
Lin, Hai
Zhang, Zhaoxiong
Jia, Yangpu
Nie, Xinyang
Liu, Tong
Fu, Weihua
author_sort Sun, Weilin
collection PubMed
description BACKGROUND: There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb). METHODS: We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity. RESULTS: We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs). CONCLUSIONS: We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.
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spelling pubmed-92956582022-08-09 CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer Sun, Weilin Wang, Xi Wang, Daohan Lu, Li Lin, Hai Zhang, Zhaoxiong Jia, Yangpu Nie, Xinyang Liu, Tong Fu, Weihua J Immunother Cancer Basic Tumor Immunology BACKGROUND: There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb). METHODS: We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity. RESULTS: We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs). CONCLUSIONS: We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs. BMJ Publishing Group 2022-07-15 /pmc/articles/PMC9295658/ /pubmed/35851310 http://dx.doi.org/10.1136/jitc-2022-005063 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Basic Tumor Immunology
Sun, Weilin
Wang, Xi
Wang, Daohan
Lu, Li
Lin, Hai
Zhang, Zhaoxiong
Jia, Yangpu
Nie, Xinyang
Liu, Tong
Fu, Weihua
CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title_full CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title_fullStr CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title_full_unstemmed CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title_short CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer
title_sort cd40×her2 bispecific antibody overcomes the ccl2-induced trastuzumab resistance in her2-positive gastric cancer
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295658/
https://www.ncbi.nlm.nih.gov/pubmed/35851310
http://dx.doi.org/10.1136/jitc-2022-005063
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