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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

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 4

Tumor-associated lymphatic vessels correlate with expression of local inflammatory mediators.

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Tumor-associated lymphatic vessels correlate with expression of local in...
(A) The expression of common inflammatory mediators in tumor microenvironments was assessed by cytokine array on tumor tissue lysates from B16F10 melanomas grown in WT or K14-VEGFR3-Ig (Tg) mice (n = 7). Relative intensity as compared with internal biotin-conjugated IgG control. Results were compared using Student’s unpaired t tests. *P < 0.05, **P < 0.01, ***P < 0.001. (B) In human metastatic cutaneous melanoma, lymphatic score (LS) correlated with gene expression of inflammatory cytokines. Box plots generated by segregating samples into 3 groups: LSlo, LSmid, and LShi. Box plots show data within 5–95 percentile with outliers shown as dots. One-way ANOVA followed by Tukey’s multiple comparisons test was used to determine significance on 266 samples. *P < 0.05, ***P < 0.005.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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