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Targeted Degradation of sGRP78 Alleviates the Immunosuppressive Tumor Microenvironment
Zhenghao Wu1,2, Peng Zheng1,2, Yunxiao Xiao1,2
1Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
There is an urgent need for appropriate methods to identify patients who are sensitive to neoadjuvant therapy (NAT) for precise stratified treatment. Based on clinical proteomics screening and further validation in patient cohorts, we reported that soluble glucose-regulatory protein 78 (sGRP78) could be a serological biomarker to infer the poor chemotherapy response in breast cancer. Consequently, an "sGRP78 index" was established to accurately predict patient responses to NAT. When exploring the linked mechanisms on how sGRP78 confer the resistance, it was found that in high sGRP78 index tumors, there were more IL-10+/PD-L1+ B subsets and Tregs infiltration, accompanied by accelerated tumor progression and metastasis. The following experiment revealed that sGRP78 bound with tumor-infiltrating B cells, converting the latter into IL-10+/PD-L1+ ones, thereby promoting Treg formation and suppressing T cell-mediated antitumor cytotoxicity. By fusing the GRP78-selective protease subtilase cytotoxin catalytic A subunit (subA) with a nanobody against HER2, we achieved the targeted degradation of sGRP78 within the breast cancer region, effectively reversing the immunosuppressive microenvironment. Our findings highlight the potential of sGRP78 index as a predictive signature to identify patients' sensitivity to NAT, as well as the potential of sGRP78 as a novel immune checkpoint target for cancer therapy.
Insights
A new "sGRP78 index" predicts breast cancer patients’ response to neoadjuvant therapy (NAT). High levels indicate poor response, suggesting soluble glucose-regulatory protein 78 (sGRP78) as a potential therapeutic target.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Accurate prediction of neoadjuvant therapy (NAT) response is crucial for personalized breast cancer treatment.
- Current methods lack sufficient precision for identifying patients likely to benefit from NAT.
Purpose of the Study:
- To identify a novel serological biomarker for predicting chemotherapy response in breast cancer patients undergoing NAT.
- To investigate the underlying mechanisms of therapy resistance mediated by the identified biomarker.
- To explore therapeutic strategies targeting the resistance mechanism.
Main Methods:
- Clinical proteomics screening and patient cohort validation to identify biomarkers.
- Development of an
- sGRP78 index
- for response prediction.
- In vitro and in vivo experiments to elucidate the role of sGRP78 in tumor immunity and resistance.
- Development of a targeted therapy using a HER2-specific nanobody fused with a GRP78-cleaving protease.
Main Results:
- Soluble glucose-regulatory protein 78 (sGRP78) was identified as a biomarker for poor response to NAT in breast cancer.
- High sGRP78 index correlated with increased IL-10+/PD-L1+ B cell subsets, Treg infiltration, tumor progression, and metastasis.
- sGRP78 promotes immunosuppression by converting B cells to an IL-10+/PD-L1+ phenotype, fostering Treg formation and inhibiting T cell cytotoxicity.
- Targeted degradation of sGRP78 reversed the immunosuppressive tumor microenvironment.
Conclusions:
- The sGRP78 index is a promising predictive signature for identifying breast cancer patients' sensitivity to NAT.
- sGRP78 plays a critical role in mediating chemotherapy resistance and immune evasion.
- sGRP78 represents a novel therapeutic target for overcoming resistance and enhancing antitumor immunity in breast cancer.
