Abstract B075: Harnessing Tumor-Penetrating Peptides to Modulate the Pancreatic Tumor Immune Microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of approximately 13% and remains largely resistant to immunotherapy because its dense fibrotic stroma restricts drug penetration, and its immunosuppressive tumor microenvironment (TME) limits anti-tumor immunity. Novel strategies are urgently needed to enhance treatment efficacy. Phage display bio-panning has identified peptides like iRGD and Lyp-1 that penetrate tumors selectively and improve drug delivery while sparing normal tissue. Using orthotopic KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse models, three-dimensional KPC spheroids, and ex vivo murine and human PDAC slice cultures, we evaluated their effects on therapeutic delivery and subsequent immune modulation. Leveraging these peptides, our work has demonstrated that iRGD, when combined with low-dose IL-2, can be utilized to enhance intratumoral CD8+ T cell activation and cytotoxicity, leading to reduced tumor burden and prolonged survival, while avoiding systemic toxicity associated with high-dose IL-2. Separately, we demonstrated that Lyp-1 penetrated KPC spheroids through its p32/gC1qBP receptor, homed to orthotopic KPC tumors, and co-localized with F4/80+ macrophages. Lyp-1 treatment reduced intratumoral arginase-1, leading to subsequent L-arginine increases. Additionally, Lyp-1 treatment elevated circulating CCL3/macrophage inflammatory protein-1α, suggesting modulation of immune cell trafficking. Together, these findings establish iRGD and Lyp-1 as complementary platforms to improve cytokine delivery and remodel the PDAC immune microenvironment, providing a mechanistic and translational framework for peptide-based combination immunotherapies.