人体自身的免疫系统在防御外来感染、清理自身异常细胞、杀伤肿瘤细胞等方面起着非常重要的作用。细胞免疫疗法在肿瘤治疗领域逐渐得到重视，该领域的研究取得了前所未有的进步，但是肿瘤的免疫治疗中依然存在诸多问题，肿瘤细胞自身可以通过分泌多种细胞因子和炎症因子对其微环境中的免疫相关细胞进行调节，其中MDSC（myeloid-derived suppressor cell）就是有肿瘤细胞诱导的对肿瘤免疫过程其抑制作用的细胞群。该群细胞的存在大大降低了细胞免疫疗法在肿瘤治疗过程中的效果。如何抑制MDSC的活性免疫疗法中的一个重要课题。
随着exosomes领域的逐渐发展，它的作用越来越受到人们的重视，日前Renaud Seigneuric、Carmen Garrido （Researchers at INSERM, UMR 866）等人对来源于小鼠肿瘤的、来源于乳腺癌、肺癌、卵巢癌病人的样品中的exosomes进行分析发现，相比正常组织而言，肿瘤细胞分泌的exosomes表面有更高丰度的HSP70，当使用顺铂等药物刺激杀伤肿瘤细胞时，其分泌的exosomes表面HSP70的丰度会进一步提高，同时HSP70的存在可以激活TLR2进而激活MDSC。该组研究者后续使用一种寡肽对HSP70的活性区域进行遮蔽，发现该处理可以对MDSC的激活起到抑制作用。使用顺铂辅以寡肽进行治疗试验，治疗效果明显优于单一使用顺铂的处理组。这些数据都暗示着，肿瘤来源的exosomes表面HSP70分子在肿瘤细胞的免疫逃逸中起着重要的作用，抑制其活性可以提高肿瘤免疫疗法的效果，同时该种寡肽可能是一种潜在的肿瘤免疫疗法的辅剂。
注：J Natl Cancer Inst：JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE （美国国立癌症研究所杂志） IF：12.583
原文来源：Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer
Background: Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the tolllikereceptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them.
Methods: We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples andcultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS,and electron microscopy. Data were analyzed with the Student’s t and Mann-Whitney tests. All statistical tests weretwo-sided.
Results: We showed that the A8 peptide aptamer binds to the extracellular domain of membrane HSP70 and used theaptamer to capture HSP70 exosomes from cancer patient samples. The number of HSP70 exosomes was higher in cancerpatients than in healthy donors (mean, ng/mL ± SD = 3.5±1.7 vs 0.17±0.11, respectively, P = .004). Accordingly, all cancercell lines examined abundantly released HSP70 exosomes, whereas “normal” cells did not. HSP70 had higher affinity forA8 than for TLR2; thus, A8 blocked HSP70/TLR2 association and the ability of tumor-derived exosomes to activate MDSCs.Treatment of tumor-bearing C57Bl/6 mice with A8 induced a decrease in the number of MDSCs in the spleen and inhibitedtumor progression (n = 6 mice per group). Chemotherapeutic agents such as cisplatin or 5FU increase the amount ofHSP70 exosomes, favoring the activation of MDSCs and hampering the development of an antitumor immune response. Incontrast, this MDSC activation was not observed if cisplatin or 5FU was combined with A8. As a result, the antitumor effectof the drugs was strongly potentiated.
Conclusions: A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition.
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