Lymphatic Vessels and the Local T cell Responses
Recent evidence demonstrates that the lymphatic endothelium may directly influence the fate and function of naïve CD8 T cells, suggesting a direct role for these cells in modulating the immune response. Understanding the mechanisms of this interaction and further how other T cell subsets, particularly cytotoxic CD8 T cells, are influenced by the endothelium may lead to novel understanding of the biology behind local mechanisms of tissue-based immune control and evasion in cancer. We are using models of acute viral infection, chronic inflammation and cancer to interrogate the role of the lymphatic endothelium in the cutaneous immune response and test the hypothesis that remodeling of the lymphatic vasculature during inflammation functions to regulate the local immune response both facilitating immune induction but also participating in immune resolution at late time points. Understanding what causes this switch in lymphatic vessel function will be of utmost relevance to immunotherapies for both malignant and non-malignant cutaneous disease.
Whole mount imaging (left) of the mouse ear dermis during viral infection. Lymphatic vessels in green and blood vessels in red. Imaging of frozen section from murine melanoma demonstrating T cell (green) clustering around lymphatic vessels (red).
Lymphatic Vessels as a Biomarker for Melanoma Response to Therapy
While lymphatic vessel density is correlated with poor prognosis in patients and increased chance of lymph node metastasis, our understanding for how lymphatic vessels directly contribute to progression is lacking. We will explore the relationship of tumor-associated lymphangiogenesis and anti-tumor immunity to understand how a tumor hijacks normal mechanisms of tissue-based immune resolution to develop a network of immune evasion. We are collaborating with the Department of Dermatology to examine retrospective and prospective human tissues from both malignant and non-malignant cutaneous pathologies.
Lymphatic vessels (purple) are expanded in the stroma of developing human cutaneous malignancies (melanoma, squamous cell carcinoma and basal cell carcinoma).