Pluripotent stem cell derivative for expressing PD-1/PD-L1 blocker and application

Abstract

The invention discloses a pluripotent stem cell derivative for expressing a PD-1 / PD-L1 blocker and application of the pluripotent stem cell derivative. An expression sequence of the PD-1 and / or PD-L1 blocker is introduced into a genome of the pluripotent stem cell or the derivative thereof. The pluripotent stem cell for expressing the PD-1 / PD-L1 blocker or the derivative of the pluripotent stem cell can be applied to low-immunogenicity cells such as iPSCs (induced pluripotent stem cells) or differentiation into MSCs (mesenchymal stem cells) by autologous cells, can continuously express the PD-1 and / or PD-L1 blocker in vivo, and is used for treating PD-1 or PD-L1 high-expression tumors and related diseases.

Description

technical field [0001] The invention belongs to the technical field of genetic engineering, and specifically relates to a pluripotent stem cell or a derivative thereof expressing a PD-1 and / or PD-L1 blocker, and related applications. Background technique [0002] PD-1 is programmed death receptor 1, an important immunosuppressive molecule, and a member of the CD28 superfamily. PD-1 is a type I transmembrane protein, which consists of three parts: the extracellular segment, the transmembrane anchor region and the intracellular signal transduction region. It is mainly induced and expressed on the surface of activated T lymphocytes and B lymphocytes. The ligands of PD-1 are B7-H1 (PD-L1) and B7-DC (PD-L2). The combination of the two inhibits the proliferation and activation of T cells, negatively regulates the response of T cells, and belongs to inhibitory receptors. PD-L1 is often expressed on the surface of tumor cells, which binds to PD-1 on the surface of T cells, inhibits...

AI Technical Summary

Problems solved by technology

However, for this kind of cells, firstly, the types of antigens presented by HLA-I antigens are reduced by more than two-thirds, and the integrity of the antigens that can be presented is greatly and irreversibly reduced. For various tumors, viruses and other disease antigens The presentation is highly biased, and still retains a considerable degree of risk of tumorigenesis and viral infection, and the risk of disease is higher when CIITA is knocked out at the same time; secondly, 12 high-frequency immune types The ethnic differences of HLA-C antigens are very large, and only 70% of them can be accounted for in some areas through our verification and calculation. However, China, India and other populous countries do not yet have authoritative large-sample HLA data. The use of PSCs is still subject to the test of a huge matching gap; third, this method will undergo several repeated gene editing work, and at least two rounds of single-cell isolation and culture for each gene editing, the whole process requires at least six rounds of single-cell isolation and culture. Cell separation and culture, these processes are inevitable and highly probable due to multiple gene editing off-targets or chromatin instability, or various unpredictable mutations in cells due to a large number of single-cell passages and proliferations, which in turn induce various problems such as carcinogenesis and metabolic diseases

It can be seen that this type of immune compatibility program is also an expedient measure in the "transitional period", and there are still many problems that have not been better resolved

[0006] In addition, some people have designed to induce killing of donor tissues and cells after they become diseased by inducing suicide genes. The loss of suitable donor cells, tissues and organs after killing is another big problem

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