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
Yang Wang, Zhuxin Gao, Xiao‐Jiao Du, Senbiao Chen, Wangcheng Zhang, Jilong Wang, Jilong Wang, Hongjun Li, Xinyu He, Jie Cao, Jun Wang, Jun Wang
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 (pHe) responsive clustered nanoparticle (LYiClustersiPD-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 LYiClustersiPD-L1 under pHe and penetrated into the tumors to silence PD-L1 gene expression in tumor cells. Compared to monotherapy, LYiClustersiPD-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.