PD-L1 siRNA–hyaluronic acid conjugate for dual-targeted cancer immunotherapy

Suyeon Kim, Roun Heo, Seok Ho Song, Kwon Ho Song, Jung Min Shin, Se Jin Oh, Hyo Jung Lee, Jo Eun Chung, Jae Hyung Park, Tae Woo Kim

Research output: Contribution to journalArticlepeer-review

Abstract

“Foreignization” of tumor cells via delivery of a non-self foreign antigen (Ag) into tumors is an appealing strategy to initiate anti-tumor immunity that can facilitate tumor rejection by pre-existing foreign-Ag–reactive T cells. However, the immune-suppressive factors in the tumor microenvironment (TME) limit the durable and potent immune response of these cells against tumor antigens, stressing the need for improved tumor-foreignization strategies. Here, we demonstrate that blockade of programmed cell death ligand 1 (PD-L1) on both tumor cells and dendritic cells (DCs) can markedly potentiate the induction of tumor-reactive T cells, thereby strengthening the anti-tumor immunity ignited by tumor-foreignization. Specifically, we developed a polymeric nanoconjugate (PEG-HA-OVA/PPLs), consisting of siPD-L1-based polyplexes, PEGylated hyaluronic acid as the CD44-targeting moiety, and ovalbumin (OVA) as a model foreign antigen. Notably, PEG-HA-OVA/PPLs were simultaneously delivered into CD44high tumor cells and CD44high DCs, leading to efficient cross-presentation of OVA and downregulation of PD-L1 in both cell types. Importantly, the nanoconjugate not only allowed OVA-specific T cells to vigorously reject the foreignized tumor cells but also reprogrammed the TME to elicit robust T-cell responses specific to the endogenous tumor Ags, eventually generating long-lasting protective immunity. Thus, our combination strategy represents an innovative approach for the induction of potent tumor immunity via a two-step consecutive immune boost against exogenous and endogenous tumor Ags.

Original languageEnglish
Pages (from-to)226-239
Number of pages14
JournalJournal of Controlled Release
Volume346
DOIs
Publication statusPublished - 2022 Jun

Keywords

  • CD44
  • Immune evasion
  • PD-L1
  • Tumor foreignization
  • Tumor microenvironment

ASJC Scopus subject areas

  • Pharmaceutical Science

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