Metastasis remains the principal cause of cancer mortality. While lymph node status is the most significant prognostic indicator for patient outcome in human solid cancer, the lymph node is also the most common site of solid tumor metastases. Although the consequences of lymph node metastases are debated, nodal metastases present an opportunity to study immunosuppressive mechanisms found in metastatic disease. Several studies have demonstrated immunosuppression of pre-metastatic LNs, although it is unclear if preconditioning is necessary for tumor growth. However, it is not known how the LN, a pillar of immunity, responds during metastatic growth. I've found that that classical sprouting angiogenesis (as observed in the primary tumor) does not occur in metastatic lymph nodes and is therefore not necessary for metastatic outgrowth. These results offer an explanation as to why past and ongoing clinical trials using anti-angiogenesis therapy have not fared as well as predicted in patients with metastasis. Instead, specialized endothelium in metastatic lymph nodes is remodeled, preserving blood flow, but decreasing immune cell migration into the lymph node. The work proposed here aims to build a biological understanding of lymph node metastases in order to define the factors that drive disease progression and identify new therapeutic interventions to improve patient survival. Based on preliminary findings, I will test the hypothesis that lymph node metastases compromise anti-tumor immunity.
For Aim 1, I will characterize the tumor-induced changes in the lymph node microenvironment that facilitate diminished lymphocyte infiltration into tumor colonies in metastatic lymph nodes. I will also measure the ability of metastatic lymph nodes to mount an immune response during growth of lymph node metastases.
Aim 2 focuses on determining whether physical contact or soluble factors from cancer cells cause dysfunctional endothelium in metastatic lymph nodes. In order to overcome a major barrier for a successful anti-tumor immune response, Aim 3 seeks to identify molecules that will enhance T cell infiltration into tumors through upregulation of adhesion molecules needed for attachment to endothelium, and ultimately, entry into tumors. Overall, this study seeks to increase the number of anti-tumor T cells and restore their function in lymph node metastases to improve local and systemic anti-tumor immunity for cancer eradication. Collectively, these studies will contribute to understanding the progression of metastases in the lymph node and distant organs and may lead to novel therapeutics that suppress metastatic growth. The experiments proposed will lay the foundation towards my career goal of becoming an independent investigator and leader in cancer biology research.
Cancer immunotherapies have resulted in broad clinical success, as measured by higher remission rates and durable responses in patients. However, the majority of cancers are non-responsive to immunotherapies; additional studies are needed to understand mechanisms of resistance to immunotherapies. The goal of this project is to understand the mechanisms and consequences of anti-tumor T cell suppression in metastatic lymph nodes in order to develop or identify agents that will reverse this immunosuppression.
