Overcoming immunotherapy resistance in bladder cancer with a novel antibody-drug conjugate RC48
Background Immune checkpoint inhibitors have shown limited response rates in bladder cancer. RC48-antibody-drug conjugate (ADC) shows potential for combination with immune checkpoint inhibitors. This study aimed to elucidate RC48-ADC’s mechanism in sensitizing tumors to immunotherapy and identify op...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-08-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/8/e011881.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background Immune checkpoint inhibitors have shown limited response rates in bladder cancer. RC48-antibody-drug conjugate (ADC) shows potential for combination with immune checkpoint inhibitors. This study aimed to elucidate RC48-ADC’s mechanism in sensitizing tumors to immunotherapy and identify optimal combination strategies.Methods Bioinformatics (The Cancer Genome Atlas, GEO, Xiangya cohorts) analyzed correlations between HER2, immune markers, and therapy response. The h-HER2-MB49 and sg-PD-L1-MB49 cell line was generated. In vitro/vivo models assessed RC48-ADC’s impact on the tumor immune microenvironment using flow cytometry, immunofluorescence, co-culture, chemotaxis, CUT&Tag assays, transcriptomics, and ELISA. Subcutaneous tumor models evaluated combination therapies. At the clinical level, bladder cancer immune therapy cohort tissue microarrays were used, and the aforementioned mechanisms were validated using immunohistochemistry and immunofluorescence.Results HER2 expression is associated with an inhibitory tumor immune microenvironment and resistance to immunotherapy. RC48-ADC treatment can reactivate this HER2-related inhibitory tumor immune microenvironment, thereby enhancing immunotherapy effectiveness. Mechanistically, RC48-ADC reactivates the tumor immune microenvironment by reducing PD-L1 transcription via Hippo pathway activation. It also promotes the release of chemokines (CCL5, CXCL9, and CXCL14) and recruits cytotoxic T-lymphocytes. In preclinical mouse models, RC48-ADC synergized with CTLA-4 and PD-L1 antibodies.Conclusions RC48-ADC enhances immunotherapy by regulating PD-L1 through the Hippo-TAZ pathway and reactivating CD8+T cells, offering a novel combination therapeutic strategy for bladder cancer. |
|---|---|
| ISSN: | 2051-1426 |