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.