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- Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and
macromolecules. J. Exp. Med. 212 , 991–999 (2015). - Louveau, A. et al. Structural and functional features of central nervous system lymphatic
vessels. Nature 523 , 337–341 (2015). - Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by
meningeal lymphatic vasculature. Nat. Neurosci. 21 , 1380–1391 (2018). - Antila, S. et al. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med.
214 , 3645–3667 (2017). - Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and
Alzheimer’s disease. Nature 560 , 185–191(2018). - Harris, M. G. et al. Immune privilege of the CNS is not the consequence of limited antigen
sampling. Sci. Rep. 4 , 4422 (2014). - Mathieu, E., Gupta, N., Macdonald, R. L., Ai, J. & Yücel, Y. H. In vivo imaging of lymphatic
drainage of cerebrospinal fluid in mouse. Fluids Barriers CNS 10 , 35 (2013). - Fankhauser, M. et al. Tumor lymphangiogenesis promotes T cell infiltration and
potentiates immunotherapy in melanoma. Sci. Transl. Med. 9 , eaal4712 (2017). - Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast
cancer metastasis. Nat. Med. 7 , 192–198 (2001). - Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma.
N. Engl. J. Med. 370 , 699–708 (2014). - Cloughesy, T. F. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit
with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med.
25 , 477–486 (2019). - Mingozzi, F. & High, K. A. Immune responses to AAV vectors: overcoming barriers to
successful gene therapy. Blood 122 , 23–36 (2013). - Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal
escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26 ,
1509–1519 (2018). - Joukov, V. et al. Proteolytic processing regulates receptor specificity and activity of
VEGF-C. EMBO J. 16 , 3898–3911 (1997). - Zincarelli, C., Soltys, S., Rengo, G. & Rabinowitz, J. E. Analysis of AAV serotypes 1–9
mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 16 ,
1073–1080 (2008). - Zeng, J. et al. Anti-PD-1 blockade and stereotactic radiation produce long-term
survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 86 , 343–349
(2013).
17. Kim, J. E. et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results
in regression of murine gliomas. Clin. Cancer Res. 23 , 124–136 (2017).
18. Filley, A. C., Henriquez, M. & Dey, M. Recurrent glioma clinical trial, CheckMate-143: the
game is not over yet. Oncotarget 8 , 91779–91794 (2017).
19. Garzon-Muvdi, T. et al. Dendritic cell activation enhances anti-PD-1 mediated
immunotherapy against glioblastoma. Oncotarget 9 , 20681–20697 (2018).
20. Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in the setting of
glioblastoma and other intracranial tumors. Nat. Med. 24 , 1459–1468 (2018).
21. Belcaid, Z. et al. Focal radiation therapy combined with 4-1BB activation and CTLA-4
blockade yields long-term survival and a protective antigen-specific memory response in
a murine glioma model. PLoS ONE 9 , e101764 (2014).
22. Bronte, V. et al. Effective genetic vaccination with a widely shared endogenous retroviral
tumor antigen requires CD40 stimulation during tumor rejection phase. J. Immunol. 171 ,
6396–6405 (2003).
23. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic
properties of tumors associated with local immune cytolytic activity. Cell 160 , 48–61 (2015).
24. He, Y. et al. Vascular endothelial cell growth factor receptor 3-mediated activation of
lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels.
Cancer Res. 65 , 4739–4746 (2005).
25. Hirakawa, S. et al. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes
promotes tumor metastasis to distant sites. Blood 109 , 1010–1017 (2007).
26. Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
Nature 537 , 417–421 (2016).
27. Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote
tumor control in response to vaccination and checkpoint blockade immunotherapy.
Immunity 50 , 195–211 (2019).
28. Lucca, L. E. et al. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight 4 ,
124427 (2019).
29. Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1
response. Nature 545 , 60–65 (2017).
30. Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the
brain. N. Engl. J. Med. 379 , 722–730 (2018).
31. Taggart, D. et al. Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends
on extracranial disease and augmentation of CD8+ T cell trafficking. Proc. Natl Acad. Sci.
USA 115 , E1540–E1549 (2018).
32. Medawar, P. B. Immunity to homologous grafted skin. III. The fate of skin homografts
transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye.
Br. J. Exp. Pathol. 29 , 58–69 (1948).
33. Volovitz, I. et al. Split immunity: immune inhibition of rat gliomas by subcutaneous
exposure to unmodified live tumor cells. J. Immunol. 187 , 5452–5462 (2011).
34. Breslin, J. W. et al. Vascular endothelial growth factor-C stimulates the lymphatic pump
by a VEGF receptor-3-dependent mechanism. Am. J. Physiol. Heart Circ. Physiol. 293 ,
H709–H718 (2007).
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