Dermal lymphatic vessels are required for the induction of local inflammation in a B16 F10 murine melanoma

The tumor microenvironment, and its heterogeneous composition, is a major contributor to metastasis and often responsible for the varied responsiveness of tumors to therapy. Within the microenvironment, the vasculature plays an important role in regulating the influx of cellular infiltrates that contribute to the local immune response driving either immune suppression or tumor rejection. The role of pre-existing, dermal lymphatic vessels in regulating this local immune response is assumed to be the passive transport of antigen and activated dendritic cells to the sentinel draining lymph node, which leads to the induction of adaptive immunity. However, we recently demonstrated that abnormal lymphatic vessel growth, or tumor-associated lymphangiogenesis, leads to impaired adaptive immunity and limited responsiveness to immunotherapy. This led us to interrogate the immunological implications of tumor-associated lymphangiogenesis as compared to pre-existing dermal lymphatic vessels. We hypothesized that while aberrant lymphatic vessel growth is associated with immune dysfunction, the pre-existing lymphatic vasculature would be necessary for immune induction within the tumor microenvironment. To test this hypothesis we implanted B16 F10 murine melanomas into mice completely lacking dermal lymphatic vessels, K14 VEGFR3-Ig. B16 F10 tumors in K14 VEGFR3-Ig mice demonstrate impaired fluid drainage and dendritic cell transport to the sentinel node. Consequently, this lymph node lacks an inflammatory response and prophylactic dermal vaccination against a model tumor antigen is unable to induce tumor rejection. Surprisingly, however, we also observed impaired local inflammation, characterized by a lack of both inflammatory and suppressive cytokines and the absence of an immune infiltrate. All immune subsets analyzed showed a dramatic reduction in K14 VEGFR3-Ig mice, including suppressive subsets such as regulatory T cells and myeloid derived suppressor cells, which importantly function to inhibit local T cell cytotoxic activity. These changes were not, however, observed systemically and were restricted to the microenvironment of the tumor itself. As a result of the altered tumor microenvironment, which led to improved T cell function, an adoptive T cell therapy was more efficacious in animals lacking dermal lymphatic vessels. This work highlights the important role of the existing lymphatic vasculature in regulating the immune response and suggests that peripheral lymphatic vessels are not only required for lymph node activation but also necessary for the initiation of local, tissue inflammation. This abstract is also presented as Poster A42. Citation Format: Amanda Lund, Marek Wagner, Manuel Fankhauser, Helge Wiig, Melody Swartz. Dermal lymphatic vessels are required for the induction of local inflammation in a B16 F10 murine melanoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR02. doi:10.1158/1538-7445.CHTME14-PR02