This study reveals the critical role of hypoxia-induced VEGF secretion in the resistance to MUC16-targeted bispecific T-cell engagers (BITE) in ovarian cancer patients. Through systematic analysis of patient-derived samples and ovarian cancer cell line models, the study identifies mechanisms of resistance including antigen expression downregulation, increased VEGF secretion, and epithelial-mesenchymal transition (EMT). It also demonstrates that the VEGF inhibitor bevacizumab can restore anti-tumor activity of BITE, suggesting a potential therapeutic strategy to overcome resistance.
Literature Overview
This article, 'Hypoxia-induced VEGF secretion promotes resistance to bispecific T-cell engagers,' published in the journal Signal Transduction and Targeted Therapy, reviews and summarizes resistance mechanisms of MUC16/CA125-targeted bispecific antibodies in ovarian cancer treatment. By collecting patient progressive disease samples and combining CRISPR/Cas9 gene editing models with in vitro experiments, the study finds that the hypoxic tumor microenvironment not only leads to CA125 downregulation but also enhances VEGF secretion and EMT transformation, thereby suppressing BITE-mediated cytotoxicity. Additionally, the research validates the role of the VEGF inhibitor bevacizumab in restoring BITE efficacy, suggesting that combination therapy may have clinical translational potential.
Background Knowledge
Bispecific T-cell engagers (BITEs) are a novel form of immunotherapy that redirects polyclonal T cells to tumor cells by simultaneously targeting tumor-associated antigens and T-cell receptors (e.g., CD3), thereby activating T-cell-mediated tumor killing. MUC16 (CA125) is a widely expressed tumor-associated antigen in high-grade serous ovarian cancer, making it an important target for BITE therapy. However, while early clinical trials of MUC16-targeted BITEs exist, the mechanisms of resistance remain incompletely understood. The current study analyzes samples from resistant patients and identifies hypoxia as a key driver of antigen downregulation and VEGF secretion. Hypoxic microenvironments are common in solid tumors and are associated with immune suppression and resistance to therapy. This study further confirms the role of VEGF in BITE resistance and provides experimental support for combining BITE therapy with VEGF inhibition. These findings expand our understanding of BITE resistance mechanisms and suggest new directions for improving immunotherapy in solid tumors.
Research Methods and Experiments
The research team collected serum, peripheral blood mononuclear cells (PBMC), and ascites samples from patients with progressive disease following MUC16-BITE treatment. CA125 expression, VEGF secretion, and EMT markers were analyzed using Western blot, ELISA, and flow cytometry. An in vitro hypoxic culture system was employed to simulate the tumor microenvironment and assess the impact of hypoxia on CA125 expression and EMT transition. MUC16 and VEGF knockout cell lines were generated using CRISPR/Cas9 technology to validate antigen expression and resistance mechanisms. The cytotoxic activity of PBMCs under different conditions (e.g., addition of patient serum or VEGF inhibition) was further evaluated to identify the source of resistance.
Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to identify the role of hypoxia-induced VEGF secretion in BITE resistance, offering a mechanistic explanation for the limited efficacy of BITE in solid tumors. Future studies should further explore how the hypoxic microenvironment affects other BITE targets and evaluate the clinical efficacy of combining BITE with VEGF inhibitors. Additionally, the hypoxia-VEGF-EMT signaling axis may contribute to resistance in other forms of immunotherapy, warranting further investigation.
Conclusion
This study systematically analyzed the mechanisms underlying resistance to MUC16/CA125-targeted BITE in ovarian cancer patients and found that the hypoxic tumor microenvironment promotes VEGF secretion and EMT transition, leading to reduced antigen expression and suppressed T-cell-mediated cytotoxicity. The study further demonstrates that the VEGF inhibitor bevacizumab can restore BITE efficacy in vitro. These findings provide a new therapeutic strategy for overcoming BITE resistance, suggesting that targeting VEGF may enhance the clinical application of BITE in solid tumors. The study not only reveals the central role of the hypoxia-VEGF-EMT signaling axis in immune therapy resistance but also provides a theoretical basis for future combination treatment strategies.
