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當前位置:首頁  >  技術(shù)文章  >  來自胚胎干細胞的CAR-NK細胞抑制異種移植動物中人類b細胞惡性腫瘤的進展

來自胚胎干細胞的CAR-NK細胞抑制異種移植動物中人類b細胞惡性腫瘤的進展

更新時間:2025-01-27  |  點擊率:127

202410月,中國科學院動物研究所干細胞與生殖生物學國家重點實驗室;北京干細胞與再生醫(yī)學研究所;暨南大學第一附屬醫(yī)院血液科(State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China;Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, China) Qi Zhang老師研究團隊在《Cancer Immunity and Immunotherapy》上發(fā)表論文:

Hypoimmunogenic CD19 CAR-NK cells derived from embryonic stem cells suppress the progression of human B-cell malignancies in xenograft animals"

 

“來自胚胎干細胞的低免疫原性CD19 CAR-NK細胞抑制異種移植動物中人類b細胞惡性腫瘤的進展"

 

Abstract

Background: Chimeric antigen receptor (CAR) engineered natural killer (NK) cells exhibit advantages such as MHC-independent recognition and strong anti-tumor functions. However, allogeneic CAR-NK cells derived from human tissues are heterogeneous and susceptible to clearance by hosts.

Methods: We generated a B2M knockout, HLA-E and CD19 CAR ectopic expressing embryonic stem cell (ESC) line, which differentiated normally and gave rise to homogeneous CD19 CAR-NK (CD19 CAR-UiNK) cells using an organoid aggregate induction method. The CD19 CAR-UiNK were co-cultured with T cells or NK cells derived from peripheral blood mononuclear cells (PBMC) with the mismatched HLA to evaluate the immunogenicity of CD19 CAR-UiNK cells. We further assessed the therapeutic effects of CD19 CAR-UiNK cells on CD19+ tumor cells through in vitro cytotoxicity assays and in vivo animal models.

Results: The CD19 CAR-UiNK cells exhibited typical expression patterns of activating and inhibitory receptors, and crucial effector molecules of NK cells, similar to those of unmodified NK cells. In co-culture assays, the CD19 CAR-UiNK cells evaded allogeneic T cell response and suppressed allogeneic NK cell response. Functionally, the CD19 CAR-UiNK cells robustly secreted IFN-γ and TNF-α, and upregulated CD107a upon stimulation with Nalm-6 tumor cells. The CD19 CAR-UiNK cells effectively eliminated CD19+ tumor cells in vitro, including B-cell cancer cell lines and primary tumor cells from human B-cell leukemia and lymphoma. Further, the CD19 CAR-UiNK cells exhibited strong anti-tumor activity in xenograft animals.

Conclusion: We offer a strategy for deriving homogeneous and hypoimmunogenic CD19 CAR-iNK cells with robust anti-tumor effects from ESCs. Our study has significant implications for developing hypoimmunogenic CD19 CAR-NK cell therapy using human ESC as an unlimited cell source.


摘要:

背景:嵌合抗原受體(CAR)修飾的自然殺傷細胞(NK)具有不依賴mhc識別和強大的抗腫瘤功能等優(yōu)勢。然而,來源于人體組織的同種異體CAR-NK細胞是異質(zhì)的,容易被宿主清除。

 

方法:利用類器官聚集誘導法,制備B2M敲除、HLA-ECD19 CAR異位表達的胚胎干細胞(ESC)系,使其正常分化并產(chǎn)生同質(zhì)的CD19 CAR- nk CD19 CAR- uink)細胞。將CD19 CAR-UiNK細胞與HLA錯配的外周血單個核細胞(PBMC)的T細胞或NK細胞共培養(yǎng),評估CD19 CAR-UiNK細胞的免疫原性。該研究通過體外細胞毒性實驗和體內(nèi)動物模型進一步評估了CD19 CAR-UiNK細胞對CD19+腫瘤細胞的治療作用。

 

結(jié)果:CD19 CAR-UiNK細胞表現(xiàn)出與未修飾NK細胞相似的活化和抑制受體以及NK細胞關(guān)鍵效應分子的典型表達模式。在共培養(yǎng)實驗中,CD19 CAR-UiNK細胞避開了同種異體T細胞的反應,抑制了同種異體NK細胞的反應。在功能上,CD19 CAR-UiNK細胞強烈分泌IFN-γ和TNF-α,并在Nalm-6腫瘤細胞刺激下上調(diào)CD107aCD19 CAR-UiNK細胞在體外有效地清除了CD19+腫瘤細胞,包括b細胞癌細胞系和來自人b細胞白血病和淋巴瘤的原代腫瘤細胞。此外,CD19 CAR-UiNK細胞在異種移植動物中表現(xiàn)出很強的抗腫瘤活性。

 

結(jié)論:該研究提供了一種從ESCs中獲得具有強大抗腫瘤作用的均勻性和低免疫原性CD19 CAR-iNK細胞的策略。該研究的研究對開發(fā)低免疫原性CD19 CAR-NK細胞療法具有重要意義,該療法使用人類ESC作為無限細胞來源。

 

該論文中,ESC、OP9細胞、表達熒光素酶的Nalm-6細胞、從三名患者的骨髓中分離出原發(fā)性人類白血病和淋巴瘤細胞的體外培養(yǎng)是使用Ausbian特級胎牛血清完成的。


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