Lymphatic function in cancer metastasis
The goal of this study is to address the role of tumor draining lymphatic function and cancer immunity during lymphatic metastasis and ionizing radiation (IR) therapy. Metastatic cancer cells invade lymphatic vessels, traffic through collecting lymphatic vessel and enter lymph node (LN) to form metastasis. The presence of cancer cells in the tumor draining LN (TuLN) is a poor prognostic indicator of patient survival/recurrence. The TuLN functions as a site of cancer metastasis, and as a lymphoid organ to generate immune response to the primary cancer. Lymphatic contraction is the major driving force of lymphatic transport, which is driven by smooth muscle cells (SMCs). Using a novel intravital imaging system that allows for the visualization of mouse lymphatic contraction, we observed lymphatic contraction strength is suppressed when tumors reach 6-8 mm in diameter with potential or very small LN metastases. The suppressed lymphatic contraction is correlated with reduced antigen transport to TuLN. We will evaluate how cancers modulate lymphatic contraction and impact lymphatic transport of tumor antigen and tumor associated dendritic cells (TuDCs) to the TuLN. We will further assess how the impaired lymphatic transport causes immune tolerance. IR therapy is widely used to treat cancer patients. Recent studies show that the efficacy of radiation therapy depends on activating host CD8+ T cell responses. We will investigate if IR therapy boosts anti-cancer immunity by improving lymphatic function.
Aim 1. To determine if myeloid cell suppress lymphatic contraction by interruption of lymphatic smooth muscle cells. This study will reveal which population of myeloid cells interact with lymphatic vessels during cancer metastasis and how these cells interact with lymphatic smooth muscle cells to suppress its contract activity.
Aim 2. To determine if suppressed lymphatic contraction impair TuDC or lymph node CD169 macrophages acquire tumor antigen and present to T cells. This study
