Project Summary
Although cancer immunotherapy has been proclaimed a breakthrough in many types of cancer, pancreatic
ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint blockade (ICB) therapy. PDAC is
classified as immunologically “cold” tumor with pronounced presence of immunosuppressive myeloid cells.
Therefore, developing novel approaches to reprogram the PDAC tumor immune microenvironment (TiME) and
promoting immunotherapeutic efficacy are drastically needed.
A key knowledge gap in understanding the PDAC TiME is a lack of tools to visualize and monitor these
immunosuppressive myeloid cells during tumor progression and treatment. Molecular imaging approaches
provide such an opportunity through a specific cell-tracking strategy or targeting of surface molecules expressed
on immune cells. In the preliminary studies, we demonstrated that yeast-derived whole b-glucan particles (WGP)
predominately traffic to the pancreas and incite massive infiltration of myeloid cells with trained immunity
phenotype, leading to a reduction in PDAC tumor progression and prolonged survival. Trained immunity is
defined as innate immune responses that can adapt and develop a memory-like phenotype of previous infection
or vaccination. Despite these successes, mice treated with WGP eventually died even in combination with anti-
PD-L1 therapy. The overarching goal of this proposal is to develop an integrated in vivo imaging with
immunophenotyping approach to understand PDAC immune evasion mechanisms and develop more efficacious
therapy for PDAC. Three Aims are proposed. Aim 1 will determine if induction of trained immunity reprograms
pancreas myeloid cells thus reshaping their function in the PDAC TiME. We will utilize a radiolabeled WGP and
an anti-CD11b probe to track WGP trafficking and influx of myeloid cells in the pancreas. We will also test the
hypothesis that the abundance of pancreas tissue resident macrophages (TRMs), as measured by the lymphatic
vessel endothelial hyaluronan receptor (LYVE-1) probe, is a predictive marker for PDAC immune evasion and
progression. Aim 2 will determine whether combining trained immunity with anti-CD47 and/or anti-EGFR mAb
therapy promotes myeloid cell phagocytic/tumoricidal activity to maximize innate antitumor immunity. Targeted
in vivo imaging will be used to monitor phagocytosis and EGFR levels within the PDAC TiME. Aim 3 will
determine the ability of induction of trained immunity to recruit and stimulate adaptive T cells in the pancreas.
We will also determine whether combining induction of trained immunity with anti-CD47 mAb therapy will further
potentiate anti-PD-L1 therapeutic efficacy in PADC. Immuno-imaging will be used to track CD8+ T cell infiltration,
function, and PD-L1 expression within the PDAC TiME. The successful completion of this proposal will likely
provide a novel insight into understanding the mechanisms of PDAC immune evasion and treatment response
and resistance.
