PSCA is a target of chimeric antigen receptor T cells in gastric cancer

被引:34
|
作者
Wu, Di [1 ,2 ,3 ]
Lv, Jiang [2 ,3 ,4 ]
Zhao, Ruocong [2 ,3 ,5 ]
Wu, Zhiping [2 ,3 ,4 ]
Zheng, Diwei [2 ,3 ,4 ]
Shi, Jingxuan [2 ,3 ,4 ]
Lin, Simiao [2 ,3 ]
Wang, Suna [2 ,3 ]
Wu, Qiting [2 ,3 ]
Long, Youguo [2 ,3 ]
Li, Peng [2 ,3 ,6 ]
Yao, Yao [2 ,3 ]
机构
[1] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Peoples R China
[2] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Key Lab Regenerat Biol, Guangzhou 510530, Peoples R China
[3] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Guangdong Prov Key Lab Stem Cell & Regenerat Med, Guangzhou 510530, Peoples R China
[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
[5] Jinan Univ, Inst Hematol, Coll Med, Guangzhou 510632, Peoples R China
[6] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Hefei Inst Stem Cell & Regenerat Med, Guangzhou 510530, Peoples R China
基金
中国国家自然科学基金;
关键词
Chimeric antigen receptor T cells; Gastric cancer; Prostate stem cell antigen; Immunotherapy; UNIVERSAL CARS; THERAPY; IMMUNOTHERAPY;
D O I
10.1186/s40364-020-0183-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Gastric cancer is a deadly malignancy and is a prognostically unfavorable entity with restricted therapeutic strategies available. Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein widely expressed in bladder, prostate, and pancreatic cancers. Existing studies have thoroughly recognized the availability of utilizing anti-PSCA CAR-T cells in the treatment of metastatic prostate cancer and non-small-cell lung cancer. However, no previous study has investigated the feasibility of using anti-PSCA CAR-T cells to treat gastric cancer, irrespective of the proven expression of PSCA on the gastric cancer cell surface. Methods We determined the expression of PSCA in several primary tumor tissues and constructed third-generation anti-PSCA CAR-T cells. We then incubated anti-PSCA CAR-T cells and GFP-T cells with target tumor cell lines at E:T ratios of 2:1, 1:1, 1:2, and 1:4 to evaluate the therapeutic efficacy of anti-PSCA CAR-T cells in vitro. We also assayed canonical T cell activation markers after coculturing anti-PSCA CAR-T cells with target cell lines by flow cytometry. The detection of a functional cytokine profile was carried out via enzyme-linked immunosorbent assays. We then evaluated the antitumor activity of anti-PSCA CAR-T cells in vivo by establishing two different xenograft GC mouse models. Results Anti-PSCA CAR-T cells exhibited upregulated activation markers and increased cytokine production profiles related to T cell cytotoxicity in an antigen-dependent manner. Moreover, anti-PSCA CAR-T cells exhibited robust anti-tumor cytotoxicity in vitro. Importantly, we demonstrated that anti-PSCA CAR-T cells delivered by peritumoral injection successfully stunted tumor progression in vivo. However, intravenous administration of anti-PSCA CAR-T cells failed to reveal any therapeutic improvements. Conclusions Our findings corroborated the feasibility of anti-PSCA CAR-T cells and their efficacy against gastric cancer, implicating the potential of applying anti-PSCA CAR-T cells to treat GC patients in the clinic.
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页数:11
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