Cancer Immunol Res. 2021 Jul;9(7):748-764. doi: 10.1158/2326-6066.CIR-20-0784. Epub 2021 May 05.

MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell-Suppressive Functions.

Cancer immunology research

Anastasia O Gkountidi, Laure Garnier, Juan Dubrot, Julien Angelillo, Guillaume Harlé, Dale Brighouse, Ludovic J Wrobel, Robert Pick, Christoph Scheiermann, Melody A Swartz, Stéphanie Hugues

PMID: 33952631 DOI: 10.1158/2326-6066.CIR-20-0784

Abstract

Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) to function as MHC class II-restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T-cell (Treg) expansion

©2021 American Association for Cancer Research.

References

1. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61–73. - PubMed
2. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6:715–27. - PubMed
3. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87. - PubMed
4. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306. - PubMed
5. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67. - PubMed
6. De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity. 2016;45:1135–47. - PubMed
7. Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;45:1122–34. - PubMed
8. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14:159–72. - PubMed
9. Olszewski WL. The innate reaction of the human skin lymphatic system to foreign and self-antigens. Lymphat Res Biol. 2005;3:50–57. - PubMed
10. Pugh CW, MacPherson GG, Steer HW. Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med. 1983;157:1758–79. - PubMed
11. Mackay CR, Marston WL, Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med. 1990;171:801–17. - PubMed
12. Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005;5:617–28. - PubMed
13. Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P, Gonzalez SF, et al. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol. 2012;13:499–510. - PubMed
14. Berendam SJ, Koeppel AF, Godfrey NR, Rouhani SJ, Woods AN, Rodriguez AB, et al. Comparative transcriptomic analysis identifies a range of immunologically related functional elaborations of lymph node associated lymphatic and blood endothelial cells. Front Immunol. 2019;10:816. - PubMed
15. Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol. 2009;10:58–65. - PubMed
16. Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R, et al. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med. 2010;207:17–27. - PubMed
17. Mendoza A, Fang V, Chen C, Serasinghe M, Verma A, Muller J, et al. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature. 2017;546:158–61. - PubMed
18. Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol. 2011;12:1096–104. - PubMed
19. Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, et al. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol. 2009;183:1767–79. - PubMed
20. Christiansen AJ, Dieterich LC, Ohs I, Bachmann SB, Bianchi R, Proulx ST, et al. Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. Oncotarget. 2016;7:39421–35. - PubMed
21. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207:681–8. - PubMed
22. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207:689–97. - PubMed
23. Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, et al. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood. 2012;120:4772–82. - PubMed
24. Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW, Corthesy-Henrioud P, et al. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J Immunol. 2014;192:5002–11. - PubMed
25. Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun. 2015;6:6771. - PubMed
26. Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D, Suter T, et al. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4(+) T cell tolerance. J Exp Med. 2014;211:1153–66. - PubMed
27. Dubrot J, Duraes FV, Harle G, Schlaeppi A, Brighouse D, Madelon N, et al. Absence of MHC-II expression by lymph node stromal cells results in autoimmunity. Life Sci Alliance. 2018;1:e201800164. - PubMed
28. Nadafi R, Gago de Graca C, Keuning ED, Koning JJ, de Kivit S, Konijn T, et al. Lymph node stromal cells generate antigen-specific regulatory T cells and control autoreactive T and B cell responses. Cell Rep. 2020;30:4110–23. - PubMed
29. Swartz MA, Lund AW. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer. 2012;12:210–9. - PubMed
30. Lund AW, Duraes FV, Hirosue S, Raghavan VR, Nembrini C, Thomas SN, et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 2012;1:191–9. - PubMed
31. Dieterich LC, Ikenberg K, Cetintas T, Kapaklikaya K, Hutmacher C, Detmar M. Tumor-associated lymphatic vessels upregulate PDL1 to inhibit T-cell activation. Front Immunol. 2017;8:66. - PubMed
32. Lane RS, Femel J, Breazeale AP, Loo CP, Thibault G, Kaempf A, et al. IFNgamma-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin. J Exp Med. 2018;215:3057–74. - PubMed
33. Fankhauser M, Broggi MAS, Potin L, Bordry N, Jeanbart L, Lund AW, et al. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci Transl Med. 2017;9:eaal4712. - PubMed
34. Barnden MJ, Allison J, Heath WR, Carbone FR. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998;76:34–40. - PubMed
35. Bazigou E, Lyons OT, Smith A, Venn GE, Cope C, Brown NA, et al. Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J Clin Invest. 2011;121:2984–92. - PubMed
36. Lee HM, Fleige A, Forman R, Cho S, Khan AA, Lin LL, et al. IFNgamma signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells. PLoS Pathog. 2015;11:e1004635. - PubMed
37. Yang BH, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, et al. Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 2016;9:444–57. - PubMed
38. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007;204:57–63. - PubMed
39. Guery L, Dubrot J, Lippens C, Brighouse D, Malinge P, Irla M, et al. Ag-presenting CpG-activated pDCs prime Th17 cells that induce tumor regression. Cancer Res. 2014;74:6430–40. - PubMed
40. Choi I, Lee S, Hong YK. The new era of the lymphatic system: no longer secondary to the blood vascular system. Cold Spring Harb Perspect Med. 2012;2:a006445. - PubMed
41. DuPage M, Dooley AL, Jacks T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc. 2009;4:1064–72. - PubMed
42. Preibisch S, Saalfeld S, Tomancak P. Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics. 2009;25:1463–5. - PubMed
43. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034. - PubMed
44. Reith W, LeibundGut-Landmann S, Waldburger JM. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol. 2005;5:793–806. - PubMed
45. Tamburini BA, Burchill MA, Kedl RM. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat Commun. 2014;5:3989. - PubMed
46. Miragaia RJ, Gomes T, Chomka A, Jardine L, Riedel A, Hegazy AN, et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity. 2019;50:493–504. - PubMed
47. Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010;140:460–76. - PubMed
48. Ma Q, Dieterich LC, Detmar M. Multiple roles of lymphatic vessels in tumor progression. Curr Opin Immunol. 2018;53:7–12. - PubMed
49. Ma Q, Dieterich LC, Ikenberg K, Bachmann SB, Mangana J, Proulx ST, et al. Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread. Sci Adv. 2018;4:eaat4758. - PubMed
50. Lund AW, Wagner M, Fankhauser M, Steinskog ES, Broggi MA, Spranger S, et al. Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J Clin Invest. 2016;126:3389–402. - PubMed
51. Sasso MS, Mitrousis N, Wang Y, Briquez PS, Hauert S, Ishihara J, et al. Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas. Sci Adv. 2021;7:eabe4362. - PubMed
52. Cohen JN, Tewalt EF, Rouhani SJ, Buonomo EL, Bruce AN, Xu X, et al. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One. 2014;9:e87740. - PubMed
53. Magnuson AM, Kiner E, Ergun A, Park JS, Asinovski N, Ortiz-Lopez A, et al. Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. Proc Natl Acad Sci U S A. 2018;115:E10672–E10681. - PubMed
54. Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest. 2013;123:939–44. - PubMed
55. Cretney E, Kallies A, Nutt SL. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol. 2013;34:74–80. - PubMed
56. Franchini DM, Lanvin O, Tosolini M, Patras de Campaigno E, Cammas A, Pericart S, et al. Microtubule-driven stress granule dynamics regulate inhibitory immune checkpoint expression in T cells. Cell Rep. 2019;26:94–107. - PubMed
57. Peske JD, Thompson ED, Gemta L, Baylis RA, Fu YX, Engelhard VH. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat Commun. 2015;6:7114. - PubMed
58. Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med. 2010;207:1791–804. - PubMed
59. Piao W, Xiong Y, Li L, Saxena V, Smith KD, Hippen KL, et al. Regulatory T cells condition lymphatic endothelia for enhanced transendothelial migration. Cell Rep. 2020;30:1052–62. - PubMed
60. Richards H, Williams A, Jones E, Hindley J, Godkin A, Simon AK, et al. Novel role of regulatory T cells in limiting early neutrophil responses in skin. Immunology. 2010;131:583–92. - PubMed

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• Journal Article
• Research Support, Non-U.S. Gov't