Abstract 40P
Background
The efficiency of adoptively transferred natural killer (NK) cells for treating solid tumors is hindered by their difficulty in entering tumors from the bloodstream and their inability to prolong viability in the absence of IL-2. Among different sources of NK cells, we utilized genetically modified NK-92MI cells, capable of releasing IL-2 to maintain viability and overcome undesirable side effects caused by the systemic administration of exogenous IL-2. PDZ-binding kinase (PBK) has been demonstrated to play a widespread and pathophysiologically relevant role in tumorigenesis and development. However, the relationship between PBK and immunity remains unclear. The aim of this study was to investigate the effect of PBK expression on the infiltration of NK-92MI cells into ovarian tumors.
Methods
PBK expression was inhibited by HI-TOPK-032. The effects of HI-TOPK-032 on the inhibition of ovarian cancer cells by NK-92MI cells were assessed using bioluminescence intensity (BLI) and CCK-8 experiments. The necessity of direct cell contact for the upregulation of NK-92MI cell cytotoxicity was explored through a trans-well chamber device and flow cytometry. The in vivo study investigated the anti-tumor effects of combined NK-92 cells and HI-TOPK-032 treatment on OVCAR3 xenografts. The impact of HI-TOPK-032 on NK cell activation and quantity was evaluated using BLI and flow cytometry.
Results
The mRNA and protein expression of PBK in OV tissues was significantly higher than that in normal tissues, and elevated PBK expression closely correlates with a compromised immune microenvironment. In vitro and in vivo experiments both, HI-TOPK-032 was found to enhance the infiltration of NK-92MI cells into tumors. The combination of HI-TOPK-032 with NK-92MI cells demonstrated superior therapeutic effects compared to the DMSO group. Results from a trans-well chamber device suggested that direct contact, rather than cytokines, might be a necessary condition for the HI-TOPK-032-assisted infiltration of NK-92MI cells.
Conclusions
The combined treatment of NK-92 MI and the small molecule inhibitor HI-TOPK-032 demonstrated enhanced anti-tumor efficacy against ovarian cancer (OV), suggesting translational potential for clinical therapy in OV.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This study was funded by the National Natural Science Foundation of China (Grant number: 82271677) and Beijing Hospitals Authority's Ascent Plan (Code: DFL20221201) Gynecological Tumor Precise Diagnosis and Treatment Innovation Studio.
Disclosure
All authors have declared no conflicts of interest.