Lymphatic vessels regulate immune microenvironments in human and murine melanoma

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

doi:10.1172/jci79434

Cited by 163 publications

(166 citation statements)

References 60 publications

(86 reference statements)

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“…29 Our findings indicate that similar mechanisms are in place in humans, because LVD strongly correlated with CD8 + T cell infiltration in primary cutaneous melanoma as well as in metastases of draining LNs. Interestingly, these associations were found in the three different zones delimited in the primary tumor sections, implying that lymphatic activation may promote accumulation of CD8 + T cells not only around but also within the tumor mass.…”

Section: Discussionsupporting

confidence: 69%

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Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

et al. 2018

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Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.

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Section: Discussionsupporting

confidence: 69%

“…28 Finally, a recent study demonstrated that in mice lacking dermal lymphatic vessels, melanomas failed to generate an inflammatory microenvironment and lacked T cell infiltration. 29 Taken together, these findings indicate a critical role for tumor-associated lymphatics in initiating and shaping the immune response.…”

Section: Introductionmentioning

confidence: 85%

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

et al. 2018

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“…Surprisingly, a recent study of human colorectal cancers found that lymphatic vessel density at the invasive margin correlated with the cytotoxic T cell density and inversely correlated with the risk of metastasis (207). Recent analysis of The Cancer Genome Atlas data of human metastatic melanoma samples has shown a correlation between levels of lymphatic gene expression and expression of genes associated with immune infiltration (208). In a mouse model of melanoma, it was found that mice lacking dermal lymphatics showed a lower immune cell infiltrate than mice with intact lymphatic drainage, but that adoptive T cell transfer was more effective in the absence of lymphatic vessels (208).…”

Section: Role Of Lecs In Immune Suppression and Tolerancementioning

confidence: 99%

“…Recent analysis of The Cancer Genome Atlas data of human metastatic melanoma samples has shown a correlation between levels of lymphatic gene expression and expression of genes associated with immune infiltration (208). In a mouse model of melanoma, it was found that mice lacking dermal lymphatics showed a lower immune cell infiltrate than mice with intact lymphatic drainage, but that adoptive T cell transfer was more effective in the absence of lymphatic vessels (208). This finding was hypothesized to be due to the lack of T regs and suppressive macrophages in the tumor microenvironment, allowing the transferred T cells to exert their cytotoxic effects (208).…”

Section: Role Of Lecs In Immune Suppression and Tolerancementioning

confidence: 99%

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

et al. 2016

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Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host’s immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

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“…Similarly, LECs display multiple immunomodulatory roles within the tumor microenvironment. LECs induce the recruitment of regulatory T cells, alter features of tumor-associated stroma, and contribute to the immunosuppressive milieu favoring tumor growth (29, 66, 67). Additional studies are necessary to evaluate these possibilities also for liver cancers and metastases.…”

Section: Lymphatics and Liver Diseasesmentioning

confidence: 99%

The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development

Lukacs‐Kornek

2016

Front. Immunol.

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Lymphatics and lymphatic endothelial cells (LECs) possess multiple immunological functions besides affecting immune cell migration, such as inhibiting T cell proliferation and antigen presentation by dendritic cells. Moreover, they control the trans-endothelial transport of multiple molecules and antigens. Emerging evidence suggest their active involvements in immunregulation, tumor, and metastases formation. In the liver, increased lymphangiogenesis, specifically at the portal area has been associated with multiple liver diseases in particular primary biliary cirrhosis, idiopathic portal hypertension, and liver malignancies. Nevertheless, the exact role and contribution of LECs to liver diseases are poorly understood. The review summarizes the current understanding of LECs in liver diseases.

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Lymphatic vessels regulate immune microenvironments in human and murine melanoma

Cited by 163 publications

References 60 publications

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development

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Lymphatic vessels regulate immune microenvironments in human and murine melanoma

Cited by 163 publications

References 60 publications

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development

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Product

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Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma