ArticleJournal for immunotherapy of cancer2022
CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Unlocking the secrets of NPSLE: the role of dendritic cell-secreted CCL2 in blood-brain barrier disruption.Frontiers in immunology · 2024Pooled it
- OTUB2 induces M2 tumor-associated macrophage polarization and increases CD274 expression in gastric cancer cells to aggravate the progression of gastric cancer.Cell death & disease · 2026Article
- A New Paradigm of Bispecific Antibodies in Clinical Management of Gastrointestinal Cancers.Oncology research · 2026Review
- A multicenter, observational study to evaluate the safety of restarting antitumor therapy recovered from COVID-19.Future oncology (London, England) · 2026Observational
- Spatial Fibroblast-Macrophage Niches in Gastric Cancer: Mechanisms of Immune Exclusion, Therapeutic Resistance, and Targeted Intervention.OncoTargets and therapy · 2026Review
- The STAT3-ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer.Frontiers in oncology · 2026Article
- Fusobacterium nucleatum-reprogrammed adipocytes promote tumor cisplatin resistance through the CCL2-CCR2 axis in the necrotic metastatic neck nodes of head and neck carcinoma.Cell communication and signaling : CCS · 2025Article
- Prognostic and predictive significance of neutrophil/lymphocyte ratio for trastuzumab treatment efficacy in HER2-positive breast cancer.Scientific reports · 2025Article
- ZC3H12A: A Critical Mediator of Inflammation, Tumor Immunotherapy, and Metabolic-Immune Crosstalk-Implications for Disease Treatment.Biomolecules · 2025Review
- Huangqi fuling decoction inhibits the invasion and metastasis of gastric cancer via the TNF signaling pathway.Scientific reports · 2025Article
- Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.Expert opinion on emerging drugs · 2025Review
- Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.Expert opinion on emerging drugs · 2025Review
- The application of organoids in investigating immune evasion in the microenvironment of gastric cancer and screening novel drug candidates.Molecular cancer · 2025Review
- The Role of Macrophages in Various Types of Tumors and the Possibility of Their Use as Targets for Antitumor Therapy.Cancers · 2025Review
- Chemokine ligand 2: beyond chemotaxis-a multifaceted role in tumor progression.Frontiers in immunology · 2025Review
- Implication of protein post translational modifications in gastric cancer.Frontiers in cell and developmental biology · 2025Review
- Targeting tumor-associated macrophages in gastric cancer progression and therapy: insights from molecular mechanisms to therapeutic applications.Frontiers in pharmacology · 2025Review
- Cell-in-cell associated lncRNA signature predicts prognosis and immunotherapy response in gastric cancer.Frontiers in oncology · 2025Article
- Protein ubiquitination in ovarian cancer immunotherapy: The progress and therapeutic strategy.Genes & diseases · 2024Review
- An update to experimental and clinical aspects of tumor-associated macrophages in cancer development: hopes and pitfalls.Clinical and experimental medicine · 2024Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThere 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).
methodsWe 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.
resultsWe 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).
conclusionsWe 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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