한빛사 논문
성균관대학교
Suyeon Kim a,b,1, Roun Heo c,1, Seok Ho Song d,1, Kwon-Ho Song e, Jung Min Shin d, Se Jin Oh a,b, Hyo-Jung Lee a,b, Jo Eun Chung a,b, Jae Hyung Park c,d,*, Tae Woo Kim a,b,f,*
a Department of Biochemistry & Molecular Biology, Korea University College of Medicine, Seoul, South Korea b Department of Biomedical Science, Korea University College of Medicine, Seoul, South Korea c Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea d School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea e Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea f NEX-I Inc., Seoul, 05854, Republic of Korea
1 Suyeon Kim, Roun Heo and Seok Ho Song contributed equally to this work.
*Corresponding author.
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.
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