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Development of immunomodulatory six base-length non-CpG motif oligonucleotides for cancer vaccination

机译：免疫调节六种碱基长的非CpG基序寡核苷酸用于癌症疫苗的开发

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We have previously described a novel family of immunomodulatory synthetic oligonucleotides characterized by a phosphodiester backbone, a length of six bases and a 5'G(3)xG(2)3' sequence, where x is A, C, G or T. In the present study, we have evaluated whether these 5G(3)xG(2)3' oligonucleotides possess additional activities essential for adequate cancer vaccination. Immunization for the treatment of cancer requires an adjuvant, a source of tumor-associated antigen (s), for example apoptotic cancer cells, and a way to overcome the escape of tumor cells from the immune system, for example the up-regulation of Fas ligand (FasL) on the surface of cancer cells. The results show that phosphodiester 5G(3)AG(2)3' and 5'G(3)TG(2)3' oligonucleotides have a direct activity on a number of different cancer cells by inducing apoptosis (release of cytochrome C, activation of caspase-3, cleavage of poly [ADP-ribose] polymerase, degradation of nuclear mitotic apparatus protein and translocation of phophatidylserine at the cell surface). In addition, the 5G(3)AG(2)3', 5'G(3)CG(2)3', and 5'G(3)TG(2)3' oligonucleotides were found to down-regulate the levels of FasL on the surface of cancer cells. These immumomodulatory phosphodiester six base-length oligonucleotides, which are capable of inducing apoptosis in cancer cells as well as downregulating the expression of FasL at their cell surface, may have application as cancer cell vaccines.
机译：我们之前已经描述了一个新型的免疫调节合成寡核苷酸家族，其特征在于磷酸二酯主链，六个碱基的长度和5'G（3）xG（2）3'序列，其中x为A，C，G或T。在本研究中，我们评估了这些5G（3）xG（2）3'寡核苷酸是否具有足够的癌症疫苗接种必要的其他活性。免疫治疗癌症需要佐剂，肿瘤相关抗原的来源，例如凋亡的癌细胞，以及克服肿瘤细胞从免疫系统逃逸的方法，例如Fas的上调癌细胞表面上的配体（FasL）。结果表明，磷酸二酯5G（3）AG（2）3'和5'G（3）TG（2）3'寡核苷酸通过诱导细胞凋亡（释放细胞色素C，活化蛋白酶3的表达，聚[ADP-核糖]聚合酶的裂解，核有丝分裂器蛋白的降解以及磷脂酰丝氨酸在细胞表面的移位）。此外，发现5G（3）AG（2）3'，5'G（3）CG（2）3'和5'G（3）TG（2）3'寡核苷酸下调了水平FasL在癌细胞表面的作用。这些免疫调节性磷酸二酯六碱基长的寡核苷酸能够在癌细胞中诱导细胞凋亡以及下调其表面上的FasL表达，因此可以用作癌细胞疫苗。

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