Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dense extracellular matrix (ECM) surrounding tumor cells to sequester CD8⁺ T cell infiltration and prevent drug penetration. Concomitant inhibition of both the TGF-β pathway and the PD-1/PD-L1 checkpoint is a viable strategy to increase T cell infiltration and cytotoxicity. Here, we used an acidic tumor extracellular pH (pH_e) responsive clustered nanoparticle (^LYiCluster_siPD-L1) to deliver TGF-β receptor inhibitors (LY2157299) and siRNA targeting PD-L1 (siPD-L1) for PDAC stroma microenvironment regulation and antitumor immunotherapy. LY2157299 encapsulated in the hydrophobic core of the nanoparticle can effectively inhibit the activation of pancreatic stellate cells (PSCs) and result in a reduction in type I collagen. siPD-L1 adsorbed on the surface of the nanoparticle was released with small size poly(amidoamine) (PAMAM) at the surface of ^LYiCluster_siPD-L1 under pH_e and penetrated into the tumors to silence PD-L1 gene expression in tumor cells. Compared to monotherapy, ^LYiCluster_siPD-L1 significantly increased tumor infiltrating CD8⁺ T cells and provoked antitumor immunity to synergistically suppress tumor growth in both a subcutaneous Panc02 xenograft model and an orthotopic tumor model.