Abstract
Peripheral blood is a source for liquid biopsy, which can meet the requirements of pretreatment disease typing to determine precise targeted therapy and monitoring of posttreatment minimal residual disease monitoring. Compared with ctDNA and CTC, exosomes have a higher concentration, good biostability, biocompatibility, low immunogenicity, and low toxicity in peripheral blood. Tumors generally secrete a large amounts of exosomes, which have potential pathophysiological roles in tumor progression. With the continuous improvement of liquid biopsy technology, many researchers have found that exosomes are the key for tumor PD-L1 to exert its role, which may be the mechanism that leads to PD-L1 and/or PD-1 inhibitor therapy resistance. Namely, tumor-derived exosomes may mediate systemic immunosuppression against PD-1 or PD-L1 inhibitor therapy, endogenous tumor cell–derived exosomal PD-L1, and tumor microenvironment–derived exosomes. Induction of PD-L1 by exosomes may be a crucial mechanisms of exosome-mediated antitumor immune tolerance. This article reviews the relationship between the detection of peripheral blood exosomal PD-L1 and tumor progression and the mechanism of exosomal PD-L1 in tumor immunotherapy.
Authors’ Contributions: Rui Wang conceived the study hypothesis and drafted the manuscript. Yanjia Yang reviewed the literature and drafted the manuscript. Jiajun Huang contributed to drawing the figures and drafting the manuscript. Yandan Yao conceived the study hypothesis, revised it critically for important intellectual content, and supervised the writing of the manuscript. All the authors read and approved the final manuscript.
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References
Saini A, Pershad Y, Albadawi H, Kuo M, Alzubaidi S, Naidu S, Knuttinen MG, Oklu R (2018) Liquid biopsy in gastrointestinal cancers. Diagnostics (Basel, Switzerland) 8(4):75
Whiteside TL (2016) Exosomes and tumor-mediated immune suppression. J Clin Invest 126(4):1216–1223
Pegtel DM, Gould SJ (2019) Exosomes. Annu Rev Biochem 88:487–514
Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M (2011) Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica 96(9):1302–1309
Dabitao D, Margolick JB, Lopez J, Bream JH (2011) Multiplex measurement of proinflammatory cytokines in human serum: comparison of the Meso Scale Discovery electrochemiluminescence assay and the Cytometric Bead Array. J Immunol Methods 372(1–2):71–77
Dai J, Su Y, Zhong S, Cong L, Liu B, Yang J, Tao Y, He Z, Chen C, Jiang Y (2020) Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther 5(1):145
Ariston Gabriel AN, Wang F, Jiao Q, Yvette U, Yang X, Al-Ameri SA, Du L, Wang YS, Wang C (2020) The involvement of exosomes in the diagnosis and treatment of pancreatic cancer. Mol Cancer 19(1):132
Wang J, Ni J, Beretov J, Thompson J, Graham P, Li Y (2020) Exosomal microRNAs as liquid biopsy biomarkers in prostate cancer. Crit Rev Oncol Hematol 145:102860
Zhang Z, Tang Y, Song X, Xie L, Zhao S, Song X (2020) Tumor-derived exosomal miRNAs as diagnostic biomarkers in non-small cell lung cancer. Front Oncol 10:560025
Xu YF, Hannafon BN, Zhao YD, Postier RG, Ding WQ (2017) Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget 8(44):77028–77040
Goto T, Fujiya M, Konishi H, Sasajima J, Fujibayashi S, Hayashi A, Utsumi T, Sato H, Iwama T, Ijiri M, Sakatani A, Tanaka K, Nomura Y, Ueno N, Kashima S, Moriichi K, Mizukami Y, Kohgo Y, Okumura T (2018) An elevated expression of serum exosomal microRNA-191, − 21, −451a of pancreatic neoplasm is considered to be efficient diagnostic marker. BMC Cancer 18(1):116
Abue M, Yokoyama M, Shibuya R, Tamai K, Yamaguchi K, Sato I, Tanaka N, Hamada S, Shimosegawa T, Sugamura K, Satoh K (2015) Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol 46(2):539–547
Moloudizargari M, Hekmatirad S, Mofarahe ZS, Asghari MH (2021) Exosomal microRNA panels as biomarkers for hematological malignancies. Curr Probl Cancer 45(5):100726
Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H, Watanabe M, Nakagama H, Yokota J, Kohno T, Tsuchiya N (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One 9(4):e92921
Lan F, Qing Q, Pan Q, Hu M, Yu H, Yue X (2018) Serum exosomal miR-301a as a potential diagnostic and prognostic biomarker for human glioma. Cell Oncol (Dordr) 41(1):25–33
Yuan X, Qian N, Ling S, Li Y, Sun W, Li J, Du R, Zhong G, Liu C, Yu G, Cao D, Liu Z, Wang Y, Qi Z, Yao Y, Wang F, Liu J, Hao S, Jin X, Zhao Y, Xue J, Zhao D, Gao X, Liang S, Li Y, Song J, Yu S, Li Y (2021) Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells. Theranostics 11(3):1429–1445
Liang Y, Song X, Li Y, Chen B, Zhao W, Wang L, Zhang H, Liu Y, Han D, Zhang N, Ma T, Wang Y, Ye F, Luo D, Li X, Yang Q (2020) LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer 19(1):85
Lee YR, Kim G, Tak WY, Jang SY, Kweon YO, Park JG, Lee HW, Han YS, Chun JM, Park SY, Hur K (2019) Circulating exosomal noncoding RNAs as prognostic biomarkers in human hepatocellular carcinoma. Int J Cancer 144(6):1444–1452
Baassiri A, Nassar F, Mukherji D, Shamseddine A, Nasr R, Temraz S (2020) Exosomal non coding RNA in LIQUID biopsies as a promising biomarker for colorectal cancer. Int J Mol Sci 21(4):1398
Yousefi H, Maheronnaghsh M, Molaei F, Mashouri L, Reza Aref A, Momeny M, Alahari SK (2020) Long noncoding RNAs and exosomal lncRNAs: classification, and mechanisms in breast cancer metastasis and drug resistance. Oncogene 39(5):953–974
Wang Y, Li Z, Xu S, Guo J (2020) Novel potential tumor biomarkers: Circular RNAs and exosomal circular RNAs in gastrointestinal malignancies. J Clin Lab Anal 34(7):e23359
Wang S, Dong Y, Gong A, Kong H, Gao J, Hao X, Liu Y, Wang Z, Fan Y, Liu C, Xu W (2021) Exosomal circRNAs as novel cancer biomarkers: challenges and opportunities. Int J Biol Sci 17(2):562–573
Ji J, Chen R, Zhao L, Xu Y, Cao Z, Xu H, Chen X, Shi X, Zhu Y, Lyu J, Jiang J, Wang Y, Zhou T, He J, Wei X, Wu JB, Yang B, Wang F (2021) Circulating exosomal mRNA profiling identifies novel signatures for the detection of prostate cancer. Mol Cancer 20(1):58
Del Re M, Cucchiara F, Rofi E, Fontanelli L, Petrini I, Gri N, Pasquini G, Rizzo M, Gabelloni M, Belluomini L, Crucitta S, Ciampi R, Frassoldati A, Neri E, Porta C, Danesi R (2021) A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC. Cancer Immunol Immunother 70(6):1667–1678
Li W, Li C, Zhou T, Liu X, Liu X, Li X, Chen D (2017) Role of exosomal proteins in cancer diagnosis. Mol Cancer 16(1):145
Theodoraki MN, Yerneni SS, Hoffmann TK, Gooding WE, Whiteside TL (2018) Clinical significance of PD-L1(+) exosomes in plasma of head and neck cancer patients. Clin Cancer Res 24(4):896–905
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H, Man Q, Zhong W, Antelo LF, Wu B, Xiong X, Liu X, Guan L, Li T, Liu S, Yang R, Lu Y, Dong L, McGettigan S, Somasundaram R, Radhakrishnan R, Mills G, Lu Y, Kim J, Chen YH, Dong H, Zhao Y, Karakousis GC, Mitchell TC, Schuchter LM, Herlyn M, Wherry EJ, Xu X, Guo W (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560(7718):382–386
Cordonnier M, Nardin C, Chanteloup G, Derangere V, Algros MP, Arnould L, Garrido C, Aubin F, Gobbo J (2020) Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J Extracell Vesicles 9(1):1710899
Li C, Li C, Zhi C, Liang W, Wang X, Chen X, Lv T, Shen Q, Song Y, Lin D, Liu H (2019) Clinical significance of PD-L1 expression in serum-derived exosomes in NSCLC patients. J Transl Med 17(1):355
Del Re M, Marconcini R, Pasquini G, Rofi E, Vivaldi C, Bloise F, Restante G, Arrigoni E, Caparello C, Bianco MG, Crucitta S, Petrini I, Vasile E, Falcone A, Danesi R (2018) PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br J Cancer 118(6):820–824
Kibria G, Ramos EK, Lee KE, Bedoyan S, Huang S, Samaeekia R, Athman JJ, Harding CV, Lötvall J, Harris L, Thompson CL, Liu H (2016) A rapid, automated surface protein profiling of single circulating exosomes in human blood. Sci Rep 6:36502
Pang Y, Shi J, Yang X, Wang C, Sun Z, Xiao R (2020) Personalized detection of circling exosomal PD-L1 based on Fe(3)O(4)@TiO(2) isolation and SERS immunoassay. Biosens Bioelectron 148:111800
Huang M, Yang J, Wang T, Song J, Xia J, Wu L, Wang W, Wu Q, Zhu Z, Song Y, Yang C (2020) Homogeneous, low-volume, efficient, and sensitive quantitation of circulating exosomal PD-L1 for cancer diagnosis and immunotherapy response prediction. Angew Chem Int Ed Engl 59(12):4800–4805
Yang Y, Li CW, Chan LC, Wei Y, Hsu JM, Xia W, Cha JH, Hou J, Hsu JL, Sun L, Hung MC (2018) Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth. Cell Res 28(8):862–864
Yu P, Steel JC, Zhang M, Morris JC, Waitz R, Fasso M, Allison JP, Waldmann TA (2012) Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model. Proc Natl Acad Sci U S A 109(16):6187–6192
Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R (2019) Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 177(2):414–427.e13
Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125(9):3384–3391
Morrissey SM, Yan J (2020) Exosomal PD-L1: roles in tumor progression and immunotherapy. Trends Cancer 6(7):550–558
Monypenny J, Milewicz H, Flores-Borja F, Weitsman G, Cheung A, Chowdhury R, Burgoyne T, Arulappu A, Lawler K, Barber PR, Vicencio JM, Keppler M, Wulaningsih W, Davidson SM, Fraternali F, Woodman N, Turmaine M, Gillett C, Franz D, Quezada SA, Futter CE, Von Kriegsheim A, Kolch W, Vojnovic B, Carlton JG, Ng T (2018) ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation. Cell Rep 24(3):630–641
Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, Nakashima H, Hayes JL, Lee K, Balaj L, Passaro C, Rooj AK, Krasemann S, Carter BS, Chen CC, Steed T, Treiber J, Rodig S, Yang K, Nakano I, Lee H, Weissleder R, Breakefield XO, Godlewski J, Westphal M, Lamszus K, Freeman GJ, Bronisz A, Lawler SE, Chiocca EA (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 4(3):eaar2766
Ning Y, Shen K, Wu Q, Sun X, Bai Y, Xie Y, Pan J, Qi C (2018) Tumor exosomes block dendritic cells maturation to decrease the T cell immune response. Immunol Lett 199:36–43
Escors D, Gato-Cañas M, Zuazo M, Arasanz H, García-Granda MJ, Vera R, Kochan G (2018) The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther 3:26
Bardhan K, Anagnostou T, Boussiotis VA (2016) The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol 7:550
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553
Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA (2012) Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 5(230):ra46
Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA (2013) PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol 33(16):3091–3098
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D (2004) PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574(1–3):37–41
Nakamura S, Hayashi K, Imaoka Y, Kitamura Y, Akazawa Y, Tabata K, Groen R, Tsuchiya T, Yamasaki N, Nagayasu T, Fukuoka J (2017) Intratumoral heterogeneity of programmed cell death ligand-1 expression is common in lung cancer. PLoS One 12(10):e0186192
Rasihashemi SZ, Rezazadeh Gavgani E, Majidazar R, Seraji P, Oladghaffari M, Kazemi T, Lotfinejad P (2021) Tumor-derived exosomal PD-L1 in progression of cancer and immunotherapy. J Cell Physiol 237:1648
Acknowledgments
This work was supported by grants from the Fundamental Research Funds for the Central Universities (20ykjc03), the National Science Foundation of China (82071859), and Guangdong Innovation and Entrepreneurship Team Projects (2019BT02Y198).
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Wang, R., Yang, Y., Huang, J., Yao, Y. (2023). The Detection of Exosomal PD-L1 in Peripheral Blood. In: Huang, T., Yang, J., Tian, G. (eds) Liquid Biopsies. Methods in Molecular Biology, vol 2695. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3346-5_13
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DOI: https://doi.org/10.1007/978-1-0716-3346-5_13
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