Reprogramming Antigen Presenting Cells in Lymph Nodes to Overcome Tumor Immune Tolerance

Abstract public domain (NIH RePORTER)

Abstract: Most cancer-related deaths are a consequence of metastatic disease. Yet, our understanding of the underlying mechanisms responsible for metastasis—especially the immune system's role in modulating metastatic progression—remains rudimentary. My sponsor’s lab recently discovered that tumor invasion into lymph nodes (LNs) evokes the induction of regulatory T cells (Tregs) that confers systemic, tumor-specific immune tolerance, thereby permitting distant (organ) metastases. While both human and murine tumor-involved lymph node tissues have demonstrated a conserved and dominant mechanism requiring Tregs for metastatic progression, the underlying mediator that governs their development remains enigmatic, and thus, warrants further investigation. In line with the notion that professional antigen-presenting cells (APCs) are critical for antigen-specific T cell development, my preliminary work revealed that professional APCs are differentially enriched in tumor-involved lymph nodes of mice. However, which APC population is responsible for promoting tumor-specific Treg development, and whether the tumor immune tolerance machinery can be therapeutically overcome remains to be investigated. To address these gaps in knowledge, I propose the following aims: 1) identify the APCs that potentiate LN metastasis-induced tumor-specific immune tolerance; and 2) assess therapeutic strategies that reprogram APCs to curtail metastatic progression. Using high-dimensional multiplexed imaging (CODEX), single-cell RNA-sequencing, various in vivo cell-depletion mouse models and adoptive cell transfer assays, as well as in vitro co-culture experiments, I will systematically dissect the key APC population that I hypothesize is responsible for mediating tumor-specific Treg development. To therapeutically reprogram the APCs away from tolerance induction, I will develop immunostimulatory antibody conjugates that drain into LNs and test them in mouse models of melanoma and pancreatic ductal adenocarcinoma. The proposed work aims to delineate the APC population that is responsible for mediating tumor-specific Treg induction and to advance the development of immunotherapeutic strategies to treat metastatic disease.

Public health relevance public domain (NIH RePORTER)

Project Narrative: This fellowship application seeks to discover the immune cell population that is responsible for initiating the biological process that allows tumors to spread into distant organs, with the ultimate goal of developing a therapeutic strategy to treat metastatic disease. I will utilize state-of-the-art technology and computational analysis to identify these immune cells, and develop a therapy that reprograms them away from undertaking this undesirable role. Advances from the proposed study will broadly impact cancer patients since metastatic disease is a major cause of cancer-related deaths worldwide.