Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 17, Issue 14, Pages 3850-3861Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.64630
Keywords
Gastric cancer; mesothelin; chimeric antigen receptor; NK-92; PDX
Categories
Funding
- National Natural Science Foundation of China [81873920, 82001930]
- Science and TechnologyProgram of Guangzhou [202002030135]
- PhD Start-up Fund of the Second Affiliated Hospital of Guangzhou Medical University
- Medical Scientific Research Foundation of Guangdong Province [A2020519]
- National Key R&D Program of China [2019YFA0904400]
- Shenzhen Science and Technology Project [SGDX2020110309280301]
- Science and Technology Development Fund, Macau SAR [FDCT/0015/2018/A1]
- University of Macau [MYRG2019-00069-FHS]
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The study demonstrated that MSLN-CAR NK cells exhibit strong antitumor activity and can effectively kill MSLN-positive gastric cancer cells, showing promising therapeutic potential for gastric cancer treatment. Moreover, MSLN-CAR NK cells also significantly prolonged the survival of tumor-bearing mice in both subcutaneous and intraperitoneal tumor models, indicating their potent antitumor effects in vivo. Additionally, the observations of potent antitumor effects and significant NK cell infiltration in patient-derived xenografts treated with MSLN-CAR NK cells further supported the therapeutic efficacy of MSLN-CAR NK cells for gastric cancer.
Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR NK cell efficacy. It has been reported that mesothelin (MSLN) may be an ideal immunotherapy target for gastric cancer. However, the feasibility of using anti-MSLN CAR NK cells to treat gastric cancer remains to be studied. Methods: MSLN expression in primary human gastric cancer, normal tissues and cell lines were detected. MSLN and CD19 targeted CAR NK-92 (MSLN- and CD19-CAR NK) cells were constructed, purified and verified. N87, MKN-28, AGS and Huh-7 cells expressing the GFP and luciferase genes were transduced. Cell and patient-derived xenograft (PDX) were established via NSG mice. The ability of MSLN-CAR NK cells to kill MSLN-positive gastric cancer cells were evaluated in vitro and in vivo. Results: MSLN-CAR NK cells can specifically kill MSLN-positive gastric cancer cells (N87, MKN-28 and AGS), rather than MSLN negative cell (Huh-7), in vitro. Moreover, compared with parental NK-92 cells and CD19-CAR NK cells, stronger cytokine secretions were secreted in MSLN-CAR NK cells cocultured with N87, MKN-28 and AGS. Furthermore, MSLN-CAR NK cells can effectively eliminate gastric cancer cells in both subcutaneous and intraperitoneal tumor models. They could also significantly prolong the survival of intraperitoneally tumor-bearing mice. More importantly, the potent antitumor effect and considerable NK cell infiltration were observed in the patient-derived xenograft treated with MSLN-CAR NK cells, which further warranted the therapeutic effects of MSLN-CAR NK cells to treat gastric cancer. Conclusion: These results demonstrate that MSLN-CAR NK cells possess strong antitumor activity and represent a promising therapeutic approach to gastric cancer.
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