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Published on: July 26, 2017
GRP78 Nanobody-Directed Immunotoxin Activates Innate Immunity Through STING Pathway to Synergize Tumor Immunotherapy
Huifang Wang1,2, Runhua Zhou3, Chengchao Xu1
1Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Department of Nuclear Medicine, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical CollegeJinan University), Shenzhen, Guangdong, 518020, China.
Abstract:
The lack of targetable antigens poses a significant challenge in developing effective cancer-targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose-regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by therapies, offers a promising pan-cancer target. To target GRP78, nanobody C5, identified from a phage library and exhibiting high affinity for human and mouse GRP78, is utilized to develop the Pseudomonas exotoxin (PE) immunotoxin C5-PE38. C5-PE38 induced ER stress, apoptosis and immunogenic cell death in targeted cells and showed antitumor efficacy against colorectal cancer and melanoma models without obvious toxicity. Mechanistically, transcriptome profiling showed that C5-PE38 reshaped the tumor immune microenvironment with enhanced innate and adaptive immune response and response to interferon beta. Moreover, C5-PE38-induced cell death could trans-activate STING pathway in dendritic cells and macrophages, promoting CD8+ T cell infiltration. It also sensitizes both primary and metastatic melanomas to anti-PD1 therapy, partly through STING activation. Overall, this study unveils a feasible GRP78 nanobody-directed therapy strategy for single or combinatorial cancer intervention. This work finds that C5-PE38-induced cell death stimulates STING-dependent cytosolic DNA release to promote antitumor immunity, a mechanism not previously reported for PE38, providing valuable insights for its clinical use.
Insights
A novel therapy targeting glucose-regulated protein 78 (GRP78) on cancer cells shows promise. This approach enhances anti-tumor immunity and sensitizes tumors to immunotherapy, offering a new strategy for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Targetable antigens are scarce in cancer therapy development.
- Cell surface expression of glucose-regulated protein 78 (GRP78) is a potential pan-cancer target.
- Endoplasmic reticulum (ER) stress and chaperone translocation are hallmarks of malignancy.
Purpose of the Study:
- To develop and evaluate a novel immunotoxin targeting GRP78 for cancer therapy.
- To investigate the mechanism of action of the GRP78-targeted immunotoxin.
- To assess the potential of this therapy in combination with existing treatments.
Main Methods:
- Development of C5-PE38, a Pseudomonas exotoxin (PE) immunotoxin using GRP78-specific nanobody C5.
- In vitro assessment of C5-PE38-induced ER stress, apoptosis, and immunogenic cell death.
- In vivo evaluation of antitumor efficacy in colorectal cancer and melanoma models.
- Transcriptome profiling to analyze immune microenvironment modulation.
- Investigation of STING pathway activation and its effect on immune cell infiltration.
Main Results:
- C5-PE38 demonstrated high affinity for GRP78 and induced cancer cell death.
- Antitumor efficacy was observed in preclinical models with minimal toxicity.
- C5-PE38 modulated the tumor immune microenvironment, enhancing innate and adaptive immunity.
- The therapy activated the STING pathway, promoting CD8+ T cell infiltration.
- Combination with anti-PD1 therapy showed enhanced efficacy in melanoma models.
Conclusions:
- GRP78 nanobody-directed therapy (C5-PE38) is a feasible strategy for single or combination cancer intervention.
- C5-PE38 induces antitumor immunity via STING-dependent mechanisms, a novel finding for PE38.
- This approach offers valuable insights for the clinical application of GRP78-targeted immunotoxins.
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