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- Title
Inhibition of exosomal and soluble ULBP1 could sensitize NKG2D CAR-NK therapy in MSI endometrial cancer.
- Authors
Qing Zhang; Xinyue Ma; Changjian Qi; Qiuli Teng; Beihua Kong
- Abstract
Objective: Microsatellite instable (MSI) endometrial cancer (EC) is a good candidate for immunotherapy due to its high mutation load. Natural killer group 2 D (NKG2D) chimeric antigen receptor-natural killer (CAR-NK), as a promising immunotherapy strategy, can target multiple ligands, including UL16 binding proteins (ULBPs). However, the therapeutic effect and resistance mechanism of NKG2D CAR-NK in MSI EC have not been clearly discussed. Therefore, we aim to investigate how to enhance the sensitivity of NKG2D CAR-NK and seek synergistic treatment strategies. Methods: We searched 2 databases (The Cancer Genome Atlas and Qilu Hospital) to identify specific therapeutic targets for MSI EC. Enzyme-linked immunosorbent assay was employed to detect the exosomal and soluble ULBP1. The anti-tumor effect and resistance mechanism of NKG2D CAR-NK were confirmed using an in vitro co-culture system and in vivo models. Results: ULBP1 is upregulated in MSI EC and indicated a poor prognosis. Exosomal and soluble ULBP1 were detected in patient serum and ULBP1 over-expressing MSI EC cell lines. The release of ULBP1 could impair the cytotoxicity and effective cytokine production of co-cultured NK cells. NKG2D CARNK was constructed and showed a more effective anti-tumor effect towards wild-type NK cells. Furthermore, induction of ULBP1 acetylation could promote its stable expression on cell membranes, reduce the secretion of free forms, and enhance therapeutic sensitivity. Conclusion: High levels of exosomal and soluble ULBP1 could potentially block the anti-tumor effect of NK cells and induce resistance to NKG2D CAR-NK therapy in MSI EC. Therefore, combined inhibition of exosomal and soluble ULBP1 production could potentially sensitize NKG2D CAR-NK therapy.
- Subjects
ENDOMETRIAL cancer; EXOSOMES; KILLER cells; ENZYME-linked immunosorbent assay; LIGANDS (Biochemistry); CHIMERIC proteins
- Publication
Journal of Gynecologic Oncology, 2024, Vol 35, p25
- ISSN
2005-0380
- Publication type
Article
- DOI
10.3802/jgo.2024.35.S2.P10