Kwak, Seo Young Lee, Seonmin Han, Hee Dong Chang, Suhwan Kim, Kyu-pyo Ahn, Hyung Jun 2024-01-19T18:33:43Z 2024-01-19T18:33:43Z 2021-09-05 2019-12 1543-8384 https://pubs.kist.re.kr/handle/201004/119268 Tumor-infiltrating T lymphocytes highly express programmed cell death protein-1 (PD-1) that interacts with its ligand, programmed cell death protein ligand-1 (PD-L1) on tumors. PD-1/PD-L1 interactions cause functional exhaustion of effector T cells and impair antitumor immunity, allowing tumors to escape immune surveillance. In addition to such extrinsic interactions, tumors proliferate by transmitting intrinsic PD-L1 signals via the mTOR pathway. Here, we simultaneously silenced PD-1 and PD-L1 expressions on CTLs and colon tumors using PD-1 siRNA/PD-L1 siRNA-loaded PLGA nanoparticles and investigated functional activation of tumor-specific CTLs. When compared to a single PD-1 silencing on CTLs or a single PD-L1 silencing on tumors, cosilencing of PD-1/PD-L1 on CTLs and tumors more efficiently promoted effector functions of tumor-specific CTLs. Moreover, PD-L1 silenced tumors inhibited mTOR signaling and showed an antiproliferative response independent of the adaptive immune response. Ultimately, systemic administration of PD-1 and PD-L1 siRNA via PLGA nanoparticles restored the effector functions of tumor-specific CTLs in MC38 tumor-bearing mice. Compared with antitumor effects of single silencing of PD-1 or PD-L1 alone, cosilencing of PD-1 and PD-L1 showed more significant tumor growth suppression and long-term tumor inhibition in colon cancer. Thus, this study provides an efficient therapeutic strategy for achieving immunotherapy in colon cancer. English AMER CHEMICAL SOC IMMUNE CHECKPOINT BLOCKADE CANCER-IMMUNOTHERAPY OVARIAN-CANCER DELIVERY RECEPTOR DRUG HETEROGENEITY THERAPEUTICS EXPRESSION BIOMARKERS PLGA Nanoparticles Codelivering siRNAs against Programmed Cell Death Protein-1 and Its Ligand Gene for Suppression of Colon Tumor Growth Article 10.1021/acs.molpharmaceut.9b00826 1 MOLECULAR PHARMACEUTICS, v.16, no.12, pp.4940 - 4953 MOLECULAR PHARMACEUTICS 16 12 4940 4953 scie scopus 000500650500017 2-s2.0-85074913594 Medicine, Research & Experimental Pharmacology & Pharmacy Research & Experimental Medicine Pharmacology & Pharmacy Article IMMUNE CHECKPOINT BLOCKADE CANCER-IMMUNOTHERAPY OVARIAN-CANCER DELIVERY RECEPTOR DRUG HETEROGENEITY THERAPEUTICS EXPRESSION BIOMARKERS siRNA delivery immune checkpoint PD-1/PD-L1 interaction cosilencing antitumor immunity colon cancer