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幾乎所有細(xì)胞都分泌細(xì)胞外囊泡（EVs），它們包含蛋白質(zhì)，脂質(zhì)和核酸，它們從親本細(xì)胞傳遞到受體細(xì)胞。因此，它們充當(dāng)細(xì)胞間通訊和分子轉(zhuǎn)移的介質(zhì)。最近的證據(jù)表明，外泌體（EV的一小部分）參與許多生理和病理過程，甚至在癌癥發(fā)生和轉(zhuǎn)移之前，它們?cè)谥厮苣[瘤免疫微環(huán)境中也起著至關(guān)重要的作用。來(lái)自腫瘤細(xì)胞和宿主細(xì)胞的外泌體在局部或遠(yuǎn)程介導(dǎo)它們的相互調(diào)節(jié)，從而確定癌癥療法的反應(yīng)性。這樣，源自腫瘤的循環(huán)外泌體被認(rèn)為是用于腫瘤的早期檢測(cè)和診斷的非侵入性生物標(biāo)記。基于外泌體的療法也正在出現(xiàn)，作為可用于抑制腫瘤進(jìn)展或增強(qiáng)抗腫瘤免疫力的前沿和有前途的策略。12月23日蘇州大學(xué)生物醫(yī)學(xué)研究所、浙江大學(xué)與浙江省腫瘤醫(yī)院團(tuán)隊(duì)在Advanced  science查看期刊詳情上發(fā)表了“Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy”，本文概述了外泌體的最新認(rèn)識(shí)及其在調(diào)節(jié)免疫應(yīng)答中的關(guān)鍵作用及其潛在的治療應(yīng)用，還介紹了當(dāng)前研究的局限性，并描述了未來(lái)研究的方向。

Figure 1:Molecular composition, biogenesis, secretion, and uptake of the exosomes. a) Exosomes contain complex contents including proteins, mRNA, miRNA, ncRNA, and DNA. TSG101 and Alix are involved in the formation of internal vesicles of MVBs. The tetraspanins such as CD9, CD63, and CD81, are the markers currently used to characterize exosomes. b) Exosomes originate from ILVs in MVBs. Firstly, proteins are transported from the Golgi or internalized from the cell surface, and nucleic acids should be endocytosed and transferred into the early endosomes. Then early endosomes maturate into late endosomes/MVB, which follow either the secretory or the degradative pathway. Microvesicles are released after formation by budding from the cytomembrane. Once released, exosomes can interact with recipient cells by direct signaling through ligand/receptor molecules on their respective surfaces. Exosomes can also be taken up by recipient cells via different manners such as direct fusion of their membrane, endocytosis, macropinocytosis, and even phagocytosis (right). Thus, exosomes function as a mode of intercellular communication and molecular transfer.

Figure 2:Functions of TEXs in tumor immune environment. a) TEXs present tumor antigen and enhance anti‐tumor immunity: in the presence of dendritic cells, TEXs loaded with specific antigens are capable of promoting the activation of tumor antigen‐specific CD8+ cytotoxic T‐lymphocytes. The HSP70 surface‐positive TEXs stimulate migratory and cytolytic activity of NK cells and macrophages. b) In most cases, TEXs function as immune suppressor. For instance, TEXs containing Fasl or TRAIL induce the apoptosis of T cells and suppress activation of T cells. TEXs bearing TGF‐β increase the proliferation of Treg cells which suppress immune responses. TEXs expressing NKG2D ligands or TGF‐β1 can inhibit the cytotoxicity of NK cells and CD8 T cells by triggering down‐regulation of their surface NKG2D expression. HSP72 bearing TEXs trigger STAT3 activation in MDSCs and promote MDSCs suppressive functions. TEXs containing miRNAs such as miR‐21‐3p, miR‐125b‐5p, miR‐181d‐5p, and miR‐1246 remodel macrophages to a tumor‐promoted phenotype

Figure 3:Mechanisms of TEXs in modulating innate and adaptive immunity. a) Tumor cell‐derived exosomal PD‐L1 can be transferred to CD8+ T cells, leading to the immunosuppression and immune escape in melanoma and prostate cancer. b) LATS1/2 deficient tumor cells secrete nucleic‐acid‐rich extracellular vesicles, which induces anti‐tumor immune responses via type I interferon. c) Tumor cell‐derived exosomal EGFR can be transferred into host macrophages to reduce their production of type I interferon and inhibit antiviral immunity. d) Primary tumor‐derived exosomal small nuclear RNAs can be transferred to the lung epithelial cells, leading to the activation of TLR3, production of chemokine, and recruitment of neutrophils. Thus, tumor‐derived exosomal small nuclear RNAs can elicit a pro‐metastatic inflammatory microenvironment by suppressing innate and adaptive anti‐tumor immunity.

Figure 4:Stroma cells in the TME support tumor progression via secreting exosomes. a) NOTCH‐MYC signaling in stromal fibroblasts shed exosomes containing unshielded RN7SL1 RNA. Upon being transferred to breast cancer cells, unshielded RN7SL1 activates RIG‐I and STAT1, and increases ISG induction, resulting in tumor growth, metastasis, and therapy resistance. Upon being transferred to immune cells, it can also drive an inflammatory response by increasing the percentage of myeloid DC populations. b) Cancer‐associated adipocytes and fibroblast‐derived exosomal miR21 can be transferred to the cancer cells, which downregulate APAF1 expression and upregulate MMP1 expression, resulting in tumor invasion and chemoresistance. c) Brain astrocyte‐derived exosomal PTEN‐targeting microRNAs can be transferred to metastatic tumor cells, induce an increased secretion of the chemokine CCL2 and facilitate the recruitment of IBA1+ myeloid cells which promotes tumor outgrowth. d) Sunitinib resistant RCC cell‐derived exosomal lncARSR can be transferred to sensitive cells and facilitates AXL and c‐MET expression, thus disseminating sunitinib resistance.

Figure 5:Exosomes from distinct immune cells play divergent roles in regulating cancer immunity. a) B cell‐derived exosomes bearing MHC II activate CD4+ T cells. DC‐derived exosomes containing tumor‐derived antigens, costimulatory molecules, and proteins, can promote the activation of CD4+ T cells and CD8+ T cells. Macrophage‐derived exosomes bearing MHC I can be transferred to DCs, thereby enabling them to activate antigen‐specific CD4+ T cells. b) Treg‐derived exosomes containing CD73 can inhibit T cell activation. CD8+ T cell‐derived exosomes carrying MHC I also mediate immune suppression by inhibiting the antigen presentation of DCs.

Figure 6：Exosomes in cancer immunotherapy. a) As exosomes have high stability in circulation and good capacity to transfer horizontal cargo, they have been explored as delivery carriers loaded with drugs or tumor targeted RNAi in different diseases. In addition, exosomes can be employed as immune modulators by expressing proteins such as SIRPα, PD1, or tumor antigen peptides. The exosomes derived from immune cells including DCs, macrophages and CD8+ T cells are demonstrated to stimulate anti‐tumor immune responses. Importantly, large‐scale generation of good manufacturing practice‐grade (GMP‐grade) and clinical‐grade exosomes are generated for clinical applications. b) Exosomes bearing GPC1, PD‐L1, or certain miRNA could be valuable as cancer biomarkers. c) Inhibition of exosomes biogenesis, release, and uptake is another strategy of cancer immunotherapy.

一、MVB排序的基礎(chǔ)機(jī)制仍然是個(gè)謎

毫無(wú)疑問，外泌體的功能由其具體含量決定，換句話說(shuō)，取決于特定運(yùn)送的貨物。盡管已在外泌體中鑒定出許多蛋白質(zhì)，但對(duì)其選擇和分類的方式知之甚少，但對(duì)于蛋白質(zhì)的外泌體積聚或貢獻(xiàn)何種特殊的翻譯后修飾（PTM）仍需了解。實(shí)際上，經(jīng)常發(fā)現(xiàn)某些但不是全部?jī)?nèi)在化的膜蛋白被吞噬進(jìn)入內(nèi)體并最終分泌為外泌體，這很可能是由于多步蛋白運(yùn)輸/分選在細(xì)胞內(nèi)囊泡運(yùn)輸過程中連續(xù)發(fā)生的結(jié)果。MVB分選過程在促進(jìn)溶酶體/真空的水解管腔內(nèi)的膜蛋白降解中起關(guān)鍵作用。盡管在過去的十年中，已經(jīng)闡明了將MVB分選為溶酶體的基本框架，但是如何將MVB分選轉(zhuǎn)換為生產(chǎn)外泌體仍然是個(gè)謎。將MVB分類到質(zhì)膜和溶酶體的機(jī)制尚不清楚，但在這兩種命運(yùn)之間存在一個(gè)決定點(diǎn)，表明對(duì)一種途徑的抑制會(huì)增加另一種途徑。細(xì)胞可能通過處理細(xì)胞來(lái)補(bǔ)償溶酶體功能障礙。潛在的有毒貨物進(jìn)入外泌體，因此，未來(lái)對(duì)MVB販運(yùn)的分子機(jī)制的研究可能會(huì)促進(jìn)當(dāng)前對(duì)致病蛋白，脂質(zhì)或傳染原如何在細(xì)胞外積聚的理解。

二、EVs中DNA的探索

與其他外泌體貨物不同，尚不清楚是否存在將特定DNA選擇性包裝入外泌體的選擇性包裝。外體DNA的功能是什么，也需要進(jìn)一步解釋。最近的研究表明，源自T細(xì)胞的外泌體包含基因組和線粒體DNA（mtDNA），該基因組和線粒體DNA從T細(xì)胞傳遞至DC以誘導(dǎo)抗病毒反應(yīng).外泌體DNA的轉(zhuǎn)移激活了cGAS / STING胞質(zhì)DNA的傳感途徑和增強(qiáng)了IRF3依賴的干擾素調(diào)節(jié)基因在DC中的表達(dá)，并且mtDNA的轉(zhuǎn)移是致癌信號(hào)，促進(jìn)了治療誘導(dǎo)的癌癥干細(xì)胞樣細(xì)胞從休眠中退出.此外，衰老細(xì)胞衍生的外泌體含有染色體DNA片段。這些結(jié)果表明，外泌體分泌可能通過去除有害的細(xì)胞質(zhì)D在維持細(xì)胞穩(wěn)態(tài)中發(fā)揮關(guān)鍵作用。細(xì)胞產(chǎn)生的NA，可防止ATM / ATR依賴的DNA損傷反應(yīng)和異常的先天免疫反應(yīng)。

盡管有關(guān)外泌體DNA的研究很多，但胞外囊泡和納米顆粒的異質(zhì)性以及純化策略的差異使外泌體的分析令人困惑。如上所述，最近的一項(xiàng)研究打破了普遍的觀點(diǎn)，即外泌體是細(xì)胞外DNA分泌的載體。

這項(xiàng)工作表明，外泌體或任何其他類型的sEV中不存在雙鏈DNA（dsDNA）和與DNA結(jié)合的組蛋白。鑒于對(duì)液體活檢中疾病的標(biāo)志物細(xì)胞外DNA的興趣日益增加，有必要重新評(píng)估實(shí)際的測(cè)量結(jié)果。但是，與傳統(tǒng)的外泌體分離方法相比，本研究中使用的更高精度的改良外泌體分離方法成本更高，效率更低。因此，迫切需要更加標(biāo)準(zhǔn)化的外泌體分離和純化技術(shù)，甚至是當(dāng)前分類和命名的修訂?？傊?，EVs的異質(zhì)性和非囊泡性細(xì)胞外納米顆粒的存在構(gòu)成了主要障礙。了解不同分泌成分的組成和功能特性。對(duì)RNA，DNA和蛋白質(zhì)的正確胞外成分及其分泌機(jī)制的更準(zhǔn)確了解對(duì)于鑒定生物標(biāo)記物和設(shè)計(jì)未來(lái)的藥物干預(yù)措施至關(guān)重要。

三、基于外泌體治療的挑戰(zhàn)

盡管外泌體在應(yīng)用方面取得了巨大成就，但挑戰(zhàn)仍然存在。由于外泌體可用作臨床生物標(biāo)志物，疫苗或藥物遞送裝置，因此迫切需要更準(zhǔn)確和標(biāo)準(zhǔn)化的純化方法。此外，為了實(shí)現(xiàn)更好的基于外泌體的免疫療法或疫苗接種，必須提高外泌體的抗原裝載效率。另一個(gè)挑戰(zhàn)是要為臨床應(yīng)用大規(guī)模生產(chǎn)外泌體。盡管已經(jīng)報(bào)道了一種從間充質(zhì)干/基質(zhì)細(xì)胞產(chǎn)生良好生產(chǎn)規(guī)范（GMP）級(jí)外泌體的生產(chǎn)方法，但該技術(shù)仍需要擴(kuò)展到其他不同的細(xì)胞類型.此外，最適合生產(chǎn)臨床級(jí)外泌體的細(xì)胞還有待進(jìn)一步研究。另外，基于外泌體的最高級(jí)療法可與其他抗腫瘤療法相結(jié)合，具有廣闊的潛力。通過外泌體的研究，可以提出更廣泛的治療應(yīng)用。