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Abstract: lymphatic vessels are essential for tissue fluid homeostasis, immune cell trafficking, and intestinal lipid absorption. The lymphatics have long been recognized to serve as conduits for distant tumor dissemination. However, recent findings suggest that the regional lymphatic vasculature also shapes the immune microenvironment of the tumor mass and potentiates immunotherapy. This review discusses the role of lymphatic vessels in tumor metastasis and tumor immunity.

淋巴血管在肿瘤转移和免疫生物学中的作用

[1]Allen F, Rauhe P, Askew D, et al., 2017. CCL3 enhances antitumor immune priming in the lymph node via IFNγ with dependency on natural killer cells. Front Immunol, 8:1390.

[2]Arbiser JL, Moses MA, Fernandez CA, et al., 1997. Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci USA, 94(3):861-866.

[3]Ariffin AB, Forde PF, Jahangeer S, et al., 2014. Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer Res, 74(10):2655-2662.

[4]Aspelund A, Robciuc MR, Karaman S, et al., 2016. Lymphatic system in cardiovascular medicine. Circul Res, 118(3):515-530.

[5]Baluk P, Fuxe J, Hashizume H, et al., 2007. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med, 204(10):2349-2362.

[6]Baluk P, Yao LC, Feng J, et al., 2009. TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest, 119(10):2954-2964.

[7]Baluk P, Hogmalm A, Bry M, et al., 2013. Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways. Am J Pathol, 182(4):1434-1447.

[8]Boardman KC, Swartz MA, 2003. Interstitial flow as a guide for lymphangiogenesis. Circul Res, 92(7):801-808.

[9]Bordry N, Broggi MAS, de Jonge K, et al., 2018. Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma. Oncoimmunology, 7(8):e1462878.

[10]Cao YH, 2005. Emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer, 5(9):735-743.

[11]Card CM, Yu SS, Swartz MA, 2014. Emerging roles of lymphatic endothelium in regulating adaptive immunity. J Clin Invest, 124(3):943-952.

[12]Chandrasekaran S, King MR, 2014. Microenvironment of tumor-draining lymph nodes: opportunities for liposome-based targeted therapy. Int J Mol Sci, 15(11):20209-20239.

[13]Chen DS, Mellman I, 2017. Elements of cancer immunity and the cancer-immune set point. Nature, 541(7637):321-330.

[14]Christiansen AJ, Dieterich LC, Ohs I, et al., 2016. Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. Oncotarget, 7(26):39421-39435.

[15]Cui Y, Liu K, Lamattina AM, et al., 2017. Lymphatic vessels: the next frontier in lung transplant. Ann Am Thorac Soc, 14(S3):S226-S232.

[16]da Mesquita S, Louveau A, Vaccari A, et al., 2018. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature, 560(7717):185-191.

[17]Dadras SS, Paul T, Bertoncini J, et al., 2003. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol, 162(6):1951-1960.

[18]Das S, Sarrou E, Podgrabinska S, et al., 2013. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. J Exp Med, 210(8):1509-1528.

[19]Dieterich LC, Ikenberg K, Cetintas T, et al., 2017. Tumor-associated lymphatic vessels upregulate PDL1 to inhibit T-cell activation. Front Immunol, 8:66.

[20]Enholm B, Paavonen K, Ristimaki A, et al., 1997. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene, 14(20):2475-2483.

[21]Fankhauser M, Broggi MAS, Potin L, et al., 2017. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci Transl Med, 9(407):eaal4712.

[22]Folkman J, 1971. Tumor angiogenesis: therapeutic implications. N Engl J Med, 285(21):1182-1186.

[23]Förster R, Davalos-Misslitz AC, Rot A, 2008. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol, 8(5):362-371.

[24]Fransen MF, Schoonderwoerd M, Knopf P, et al., 2018. Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. JCI Insight, 3(23):e124507.

[25]Gao P, Li CJ, Chang Z, et al., 2018. Carcinoma associated fibroblasts derived from oral squamous cell carcinoma promote lymphangiogenesis via c-Met/PI3K/AKT in vitro. Oncol Lett, 15(1):331-337.

[26]Guan XM, 2015. Cancer metastases: challenges and opportunities. Acta Pharm Sin B, 5(5):402-418.

[27]Harris AR, Perez MJ, Munson JM, 2018. Docetaxel facilitates lymphatic-tumor crosstalk to promote lymphangiogenesis and cancer progression. BMC Cancer, 18:718.

[28]Harvey NL, Gordon EJ, 2012. Deciphering the roles of macrophages in developmental and inflammation stimulated lymphangiogenesis. Vascular Cell, 4(1):15.

[29]Henri O, Pouehe C, Houssari M, et al., 2016. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation, 133(15):1484-1497.

[30]Hirakawa S, Kodama S, Kunstfeld R, et al., 2005. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med, 201(7):1089-1099.

[31]Hirakawa S, Brown LF, Kodama S, et al., 2007. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood, 109(3):1010-1017.

[32]Hirakawa S, Detmar M, Kerjaschki D, et al., 2009. Nodal lymphangiogenesis and metastasis: role of tumor-induced lymphatic vessel activation in extramammary Paget’s disease. Am J Pathol, 175(5):2235-2248.

[33]Hos D, Cursiefen C, 2014. Lymphatic vessels in the development of tissue and organ rejection. In: Kiefer F, Schulte-Merker S (Eds.), Developmental Aspects of the Lymphatic Vascular System. Advances in Anatomy, Embryology and Cell Biology, Vol. 214. Springer, Vienna, p.119-141.

[34]Imai T, Hieshima K, Haskell C, et al., 1997. Identification and molecular characterization of fractalkine receptor CX₃CR1, which mediates both leukocyte migration and adhesion. Cell, 91(4):521-530.

[35]Jackson DG, 2014. Lymphatic regulation of cellular trafficking. J Clin Cell Immunol, 5:258.

[36]Jeanbart L, Ballester M, de Titta A, et al., 2014. Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol Res, 2(5):436-447.

[37]Jeltsch M, Kaipainen A, Joukov V, et al., 1997. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science, 276(5317):1423-1425.

[38]Jiang XG, Shapiro DJ, 2014. The immune system and inflammation in breast cancer. Mol Cell Endocrinol, 382(1):673-682.

[39]Jiang XG, Nicolls MR, Tian W, et al., 2018. Lymphatic dysfunction, leukotrienes, and lymphedema. Ann Rev Physiol, 80:49-70.

[40]Kabashima K, Shiraishi N, Sugita K, et al., 2007a. CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol, 171(4):1249-1257.

[41]Kabashima K, Sugita K, Shiraishi N, et al., 2007b. CXCR4 engagement promotes dendritic cell survival and maturation. Biochem Biophys Res Commun, 361(4):1012-1016.

[42]Karaman S, Detmar M, 2014. Mechanisms of lymphatic metastasis. J Clin Invest, 124(3):922-928.

[43]Karlsson MC, Gonzalez SF, Welin J, et al., 2017. Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system. Mol Oncol, 11(7):781-791.

[44]Kerjaschki D, Bago-Horvath Z, Rudas M, et al., 2011. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest, 121(5):2000-2012.

[45]Kim S, Chung M, Jeon NL, 2016. Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro. Biomaterials, 78:115-128.

[46]Kimura T, Sugaya M, Oka T, et al., 2015. Lymphatic dysfunction attenuates tumor immunity through impaired antigen presentation. Oncotarget, 6(20):18081-18093.

[47]Lambert AW, Pattabiraman DR, Weinberg RA, 2017. Emerging biological principles of metastasis. Cell, 168(4):670-691.

[48]Lane RS, Femel J, Breazeale AP, et al., 2018. IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin. J Exp Med, 215(12):3057.

[49]Lee JW, Epardaud M, Sun J, et al., 2007. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol, 8(2):181-190.

[50]Lopez Gelston CA, Balasubbramanian D, Abouelkheir GR, et al., 2018. Enhancing renal lymphatic expansion prevents hypertension in mice. Circul Res, 122(8):1094-1101.

[51]Lukacs-Kornek V, Malhotra D, Fletcher AL, et al., 2011. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol, 12(11):1096-1104.

[52]Lund AW, Duraes FV, Hirosue S, et al., 2012. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep, 1(3):191-199.

[53]Lund AW, Wagner M, Fankhauser M, et al., 2016. Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J Clin Invest, 126(9):3389-3402.

[54]Mäkinen T, Norrmén C, Petrova TV, 2007. Molecular mechanisms of lymphatic vascular development. Cell Mol Life Sci, 64(15):1915-1929.

[55]Malhotra D, Fletcher AL, Astarita J, et al., 2012. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol, 13(5):499-510.

[56]Mlecnik B, Bindea G, Kirilovsky A, et al., 2016. The tumor microenvironment and immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med, 8(327):327ra26.

[57]Mortimer PS, Rockson SG, 2014. New developments in clinical aspects of lymphatic disease. J Clin Invest, 124(3):915-921.

[58]Müller A, Homey B, Soto H, et al., 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824):50-56.

[59]Nandi P, Girish GV, Majumder M, et al., 2017. PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer, 17:11.

[60]Nichols LA, Chen YM, Colella TA, et al., 2007. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol, 179(2):993-1003.

[61]Nishikawa H, Sakaguchi S, 2014. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol, 27:1-7.

[62]Nörder M, Gutierrez MG, Zicari S, et al., 2012. Lymph node-derived lymphatic endothelial cells express functional costimulatory molecules and impair dendritic cell-induced allogenic T-cell proliferation. FASEB J, 26(7):2835-2846.

[63]Paduch R, 2016. The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol, 39(5):397-410.

[64]Pflicke H, Sixt M, 2009. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med, 206(13):2925-2935.

[65]Proulx ST, Detmar M, 2013. Molecular mechanisms and imaging of lymphatic metastasis. Exp Cell Res, 319(11):1611-1617.

[66]Randolph GJ, Ivanov S, Zinselmeyer BH, et al., 2016. The lymphatic system: integral roles in immunity. Annu Rev Immunol, 35:31-52.

[67]Robbins PD, Morelli AE, 2014. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol, 14(3):195-208.

[68]Roberts EW, Broz ML, Binnewies M, et al., 2016. Critical role for CD103⁺/CD141⁺ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell, 30(2):324-336.

[69]Rockson SG, Tian W, Jiang XG, et al., 2018. Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight, 3(20):e123775.

[70]Rohner NA, McClain J, Tuell SL, et al., 2015. Lymph node biophysical remodeling is associated with melanoma lymphatic drainage. FASEB J, 29(11):4512-4522.

[71]Roozendaal R, Mempel TR, Pitcher LA, et al., 2009. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity, 30(2):264-276.

[72]Sainz-Jaspeado M, Claesson-Welsh L, 2018. Cytokines regulating lymphangiogenesis. Curr Opin Immunol, 53:58-63.

[73]Schoenborn JR, Wilson CB, 2007. Regulation of interferon-γ during innate and adaptive immune responses. Adv Immunol, 96:41-101.

[74]Schumacher TN, Schreiber RD, 2015. Neoantigens in cancer immunotherapy. Science, 348(6230):69-74.

[75]Shayan R, Achen MG, Stacker SA, 2006. Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis, 27(9):1729-1738.

[76]Shin K, Kataru RP, Park HJ, et al., 2015. T_H2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat Commun, 6:6196.

[77]Skobe M, Hawighorst T, Jackson DG, et al., 2001. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med, 7(2):192-198.

[78]Stacker SA, Caesar C, Baldwin ME, et al., 2001. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med, 7(2):186-191.

[79]Stacker SA, Williams SP, Karnezis T, et al., 2014. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer, 14(3):159-172.

[80]Stump B, Cui Y, Kidambi P, et al., 2017. Lymphatic changes in respiratory diseases: more than just remodeling of the lung? Am J Respir Cell Mol Biol, 57(3):272-279.

[81]Su WC, Shiesh SC, Liu HS, et al., 2001. Expression of oncogene products HER2/Neu and Ras and fibrosis-related growth factors bFGF, TGF-β, and PDGF in bile from biliary malignancies and inflammatory disorders. Dig Dis Sci, 46(7):1387-1392.

[82]Tammela T, Alitalo K, 2010. Lymphangiogenesis: molecular mechanisms and future promise. Cell, 140(4):460-476.

[83]Tewalt EF, Cohen JN, Rouhani SJ, et al., 2012. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood, 120(24):4772-4782.

[84]Thomas SN, Vokali E, Lund AW, et al., 2014. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials, 35(2):814-824.

[85]Thomas SN, Rohner NA, Edwards EE, 2016. Implications of lymphatic transport to lymph nodes in immunity and immunotherapy. Annu Rev Biomed Eng, 18:207-233.

[86]Tian W, Rockson SG, Jiang XG, et al., 2017. Leukotriene B₄ antagonism ameliorates experimental lymphedema. Sci Transl Med, 9(389):eaal3920.

[87]Ueba T, Nosaka T, Takahashi JA, et al., 1994. Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc Natl Acad Sci USA, 91(19):9009-9013.

[88]Uramoto H, Hackzell A, Wetterskog D, et al., 2004. pRb, Myc and p53 are critically involved in SV40 large T antigen repression of PDGF β-receptor transcription. J Cell Sci, 117(17):3855-3865.

[89]Vaahtomeri K, Karaman S, Makinen T, et al., 2017. Lymphangiogenesis guidance by paracrine and pericellular factors. Genes Dev, 31(16):1615-1634.

[90]Varricchi G, Loffredo S, Galdiero MR, et al., 2018. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol, 53:152-160.

[91]Vieira JM, Norman S, del Campo CV, et al., 2018. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest, 128(8):3402-3412.

[92]Wei R, Lv MQ, Li F, et al., 2017. Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis. Oncotarget, 8(40):67315-67328.

[93]Weichand B, Popp R, Dziumbla S, et al., 2017. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J Exp Med, 214(9):2695-2713.

[94]Wong BW, Wang XW, Zecchin A, et al., 2017. The role of fatty acid β-oxidation in lymphangiogenesis. Nature, 542(7639):49-54.

[95]Yamada A, Nagahashi M, Aoyagi T, et al., 2018. ABCC1-exported sphingosine-1-phosphate, produced by Sphingosine kinase 1, shortens survival of mice and patients with breast cancer. Mol Cancer Res, 16(6):1059-1070.

[96]Yeo KP, Angeli V, 2017. Bidirectional crosstalk between lymphatic endothelial cell and T cell and its implications in tumor immunity. Front Immunol, 8:83.

[97]Yu PC, Wilhelm K, Dubrac A, et al., 2017. FGF-dependent metabolic control of vascular development. Nature, 545(7653):224-228.

[98]Zheng W, Tammela T, Yamamoto M, et al., 2011. Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood, 118(4):1154-1162.

[99]Zheng W, Aspelund A, Alitalo K, 2014. Lymphangiogenic factors, mechanisms, and applications. J Clin Invest, 124(3):878-887.