Enhanced antigen-lymphocyte interactions to improve immune checkpoint blockade in breast cancer

点击翻译按钮获取中文摘要

Project Summary Immunotherapy, and in particular immune checkpoint blockade (ICB), has emerged as one of the most promising tools in the fight against breast cancer, with the advantages of treating both local and disseminated disease, and protecting against cancer recurrence. However, response rates to ICB have been limited clinically: only ~16% of breast cancer patients respond to ICB. ICB exerts its effects by preventing the suppression of effector anti-cancer T cells in order to maintain a strong anti-cancer immune response. Because the adaptive immune system is housed within lymphoid organs, and tumor draining lymph nodes (TDLNs) have been shown to contain higher concentrations of tumor-disseminated antigen, we hypothesize a role for TDLNs in facilitating cognate T cell- antigen interactions that lead to activation of anti-cancer T cells that are prerequisite for ICB response. I hypothesize that tumor-mediated alterations in fluid dynamics and local microenvironments alter antigen-cognate T cell interactions, which impairs ICB responses clinically. In the proposed study, I will test this hypothesis using animal models which allow for longitudinal surveillance of lymph flow and the assessment of T cells and antigen- presenting cells within lymph nodes. I will cancer models that spontaneously develop lymph node metastases in a robust manner and use immunomodulatory interventions to test interrogate the role of lymph nodes in generating anti-cancer immunity. Further, we will determine the effects of primary in situ tumors, and the presence of intra-lymph node metastases on the T cell interactions with cognate antigen in lymph nodes and the impacts of these parameters on ICB efficacy. Finally, the impacts of removal of the primary tumor—a large source of cancer antigen for development of anti-cancer responses—on T cell phenotypes and resulting ICB responses will be measured. As a whole, this work has the potential to both inform clinical standard of care, and to improve the efficacy of immune checkpoint blockade. I have extensive training in the use of animal models to investigate the tumor immunology, and in understanding how antigen is transported from tumors to lymph nodes to impact anti-tumor immune responses. This project will leverage my training and allow me to grow new expertise in the labs of my postdoctoral advisors—Dr. Padera and Dr. Munn—who are leaders in lymphatic and vascular biology as well as tumor microenvironment research. Dr. Padera’s lab has developed state-of-the-art lymphatic imaging tools to precisely measure lymph flow rate, and dynamic intravital microscopy of tumor dissemination through lymphatic vasculature and within lymph nodes. Dr. Munn’s lab has developed bioengineered models of angiogenesis and tumor biology, and sophisticated computational models of lymph nodes and lymphatic transport. Their combined guidance will allow me to successfully complete the aims of this proposal. Furthermore, the unique environment within the Steele Laboratories at Massachusetts General Hospital and Harvard Medical School will provide the training I need to take the next step toward an independent research career.