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Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy
Wenjiao Xia1, Jiaxin Chen1, Wenqing Hou1
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
Abstract:
A new therapy strategy for relapsing patients who have received trastuzumab treatment urgently needs to be explored. HER2-specific chimeric antigen receptor (CAR)-expressing NK cells are being rapidly developed for solid tumor therapy, as they have many advantages over HER2-CAR-T cells. Endogenous soluble PD-1 (sPD-1) from the PD-1 extracellular domain blocks PD-1/PD-L1 interaction to promote cancer immunology. Herein, we engineered a new HER2-CAR-NK cell that co-expresses sPD-1 (designed as sPD-1-CAR-NK cells) and assessed its cytotoxic activities toward various cancer cells, activation of immunity and sPD-1 release in vitro and in mouse models bearing breast cancer cells with high HER2 expression, with or without trastuzumab resistance. We demonstrated that sPD-1-CAR-NK cells were able to release bioactive sPD-1, thereby enhancing the cytolytic activities of HER2-CAR-NK cells against HER2 and PD-L1 highly expressing target cells accompanied by increases in the secretion of perforin, granzyme B and IFN-γ. In vivo, sPD-1-CAR-NK cells had superior immunological anticancer efficacy compared to HER2-CAR-NK cells, and they had advantages over HER2-CAR-NK cells in the intraperitoneal injection of sPD-1. Moreover, the infiltration and activation of NK and T cells into tumor tissue were increased in mice with sPD-1-CAR-NK cells. There was no significant change in the body temperature, organ tissue and body weight in all groups except for the group with the PD-1 injection. Together, these data indicate that HER2-specific sPD-1-CAR-NK cells can transport sPD-1 into cancer tissues with high HER2 expression, further improving the efficacy of HER-CAR-NK cells without obvious side effects. sPD-1-CAR-NK is a promising cytotherapeutic agent for patients bearing HER2-positive breast cancer, including those with trastuzumab resistance.
Insights
Engineered HER2-CAR-NK cells co-expressing soluble PD-1 (sPD-1) enhance cancer immunotherapy by boosting cytotoxic activity and immune cell infiltration. This novel sPD-1-CAR-NK therapy shows promise for HER2-positive breast cancer, even with trastuzumab resistance.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Trastuzumab resistance necessitates new therapies for HER2-positive breast cancer.
- Chimeric antigen receptor (CAR)-NK cells offer advantages for solid tumor treatment.
- Soluble PD-1 (sPD-1) can enhance anti-cancer immune responses by blocking PD-1/PD-L1 interactions.
Purpose of the Study:
- To engineer and evaluate HER2-specific CAR-NK cells co-expressing sPD-1 (sPD-1-CAR-NK cells).
- To assess the in vitro and in vivo efficacy of sPD-1-CAR-NK cells against HER2-positive breast cancer, including trastuzumab-resistant models.
- To investigate the impact of sPD-1-CAR-NK cells on immune cell activation and tumor microenvironment.
Main Methods:
- Engineering of HER2-CAR-NK cells to co-express sPD-1.
- In vitro assessment of sPD-1-CAR-NK cell cytotoxicity against HER2-expressing cancer cells.
- In vivo studies using mouse models of HER2-positive breast cancer to evaluate anti-tumor efficacy and immune responses.
- Analysis of cytokine secretion (perforin, granzyme B, IFN-γ) and immune cell infiltration.
Main Results:
- sPD-1-CAR-NK cells successfully released bioactive sPD-1, enhancing cytolytic activity against HER2 and PD-L1 co-expressing tumor cells.
- Enhanced secretion of perforin, granzyme B, and IFN-γ was observed with sPD-1-CAR-NK cell treatment.
- In vivo studies demonstrated superior anti-tumor efficacy of sPD-1-CAR-NK cells compared to HER2-CAR-NK cells, with increased NK and T cell infiltration into tumors.
- No significant adverse effects were observed in treated mice, indicating a favorable safety profile.
Conclusions:
- Co-expression of sPD-1 in HER2-CAR-NK cells significantly improves their anti-cancer efficacy.
- sPD-1-CAR-NK cells represent a promising therapeutic strategy for HER2-positive breast cancer, including cases resistant to trastuzumab.
- This approach offers a potential new avenue for cancer immunotherapy with enhanced safety and effectiveness.
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