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Lymphatic vessels regulate immune microenvironments in human and murine melanoma
Amanda W. Lund, … , Helge Wiig, Melody A. Swartz
Amanda W. Lund, … , Helge Wiig, Melody A. Swartz
Published August 15, 2016
Citation Information: J Clin Invest. 2016;126(9):3389-3402. https://doi.org/10.1172/JCI79434.
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Research Article Angiogenesis Article has an altmetric score of 5

Lymphatic vessels regulate immune microenvironments in human and murine melanoma

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Abstract

Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.

Authors

Amanda W. Lund, Marek Wagner, Manuel Fankhauser, Eli S. Steinskog, Maria A. Broggi, Stefani Spranger, Thomas F. Gajewski, Kari Alitalo, Hans P. Eikesdal, Helge Wiig, Melody A. Swartz

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Figure 7

Improved efficacy of adoptively transferred anti-OVA effector CD8+ T cells against OVA-expressing melanomas implanted in K14-VEGFR3-Ig mice.

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Improved efficacy of adoptively transferred anti-OVA effector CD8+ T cel...
(A) Experimental schematic. B16F10.OVA tumor cells (0.5 × 106) were injected intradermally (i.d.) into either WT or K14-VEGFR3-Ig (Tg) mice, and after 6 days, activated OT-I CD8+ T cells were injected intravenously (i.v.). Mice were sacrificed 7 days following transfer. (B) Tumor growth profiles and (C) Kaplan-Meier curve showing relative times to tumor regression (n = 5). (D and E) Flow cytometric analysis of circulatory (D) CD45+ cells or (E) OT-1 cells at day 13, and (F) IFN-γ+ T cells in spleen following restimulation. (G–K) Flow cytometric analysis of tumor infiltrating (G) leukocytes (CD45+), (H) antigen-specific CD8+ T cells (H-2Kb SIINFEKL+), and (I) IFN-γ+ CD8+ T cells following in vivo brefeldin A treatment. Box and whisker plots show data from min to max. Statistical analysis with Mann Whitney U test. *P < 0.05, **P < 0.01 in at least 2 separate experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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