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Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches

BACKGROUND: Cytotoxic CD8(+) T cell-based cancer immunotherapy has been extensively studied and applied, however, tumor cells are known to evade immune responses through the expression of immune checkpoints, such as programmed death ligand 1 (PD-L1). To overcome these issues, antibody-based immune c...

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Autores principales: Won, Ji Eun, Byeon, Youngseon, Wi, Tae In, Lee, Chan Mi, Lee, Ju Hyeong, Kang, Tae Heung, Lee, Jeong-Won, Lee, YoungJoo, Park, Yeong-Min, Han, Hee Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886443/
https://www.ncbi.nlm.nih.gov/pubmed/35228265
http://dx.doi.org/10.1136/jitc-2021-003928
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author Won, Ji Eun
Byeon, Youngseon
Wi, Tae In
Lee, Chan Mi
Lee, Ju Hyeong
Kang, Tae Heung
Lee, Jeong-Won
Lee, YoungJoo
Park, Yeong-Min
Han, Hee Dong
author_facet Won, Ji Eun
Byeon, Youngseon
Wi, Tae In
Lee, Chan Mi
Lee, Ju Hyeong
Kang, Tae Heung
Lee, Jeong-Won
Lee, YoungJoo
Park, Yeong-Min
Han, Hee Dong
author_sort Won, Ji Eun
collection PubMed
description BACKGROUND: Cytotoxic CD8(+) T cell-based cancer immunotherapy has been extensively studied and applied, however, tumor cells are known to evade immune responses through the expression of immune checkpoints, such as programmed death ligand 1 (PD-L1). To overcome these issues, antibody-based immune checkpoint blockades (eg, antiprogrammed cell death 1 (anti-PD-1) and anti-PD-L1) have been revolutionized to improve immune responses. However, their therapeutic efficacy is limited to 15%–20% of the overall objective response rate. Moreover, PD-L1 is secreted from tumor cells, which can interrupt antibody-mediated immune reactions in the tumor microenvironment. METHODS: We developed poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) encapsulating PD-L1 small interfering RNA (siRNA) and PD-1 siRNA, as a delivery platform to silence immune checkpoints. This study used the TC-1 and EG7 tumor models to determine the potential therapeutic efficacy of the PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs, on administration twice per week for 4 weeks. Moreover, we observed combination effect of PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs using TC-1 and EG7 tumor-bearing mouse models. RESULTS: PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs boosted the host immune reaction by restoring CD8(+) T cell function and promoting cytotoxic CD8(+) T cell responses. We demonstrated that the combination of NP-based therapeutic vaccine and PLGA (siRNA)-NPs resulted in significant inhibition of tumor growth compared with the control and antibody-based treatments (p<0.001). The proposed system significantly inhibited tumor growth compared with the antibody-based approaches. CONCLUSION: Our findings suggest a potential combination approach for cancer immunotherapy using PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs as novel immune checkpoint silencing agents.
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spelling pubmed-88864432022-03-17 Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches Won, Ji Eun Byeon, Youngseon Wi, Tae In Lee, Chan Mi Lee, Ju Hyeong Kang, Tae Heung Lee, Jeong-Won Lee, YoungJoo Park, Yeong-Min Han, Hee Dong J Immunother Cancer Basic Tumor Immunology BACKGROUND: Cytotoxic CD8(+) T cell-based cancer immunotherapy has been extensively studied and applied, however, tumor cells are known to evade immune responses through the expression of immune checkpoints, such as programmed death ligand 1 (PD-L1). To overcome these issues, antibody-based immune checkpoint blockades (eg, antiprogrammed cell death 1 (anti-PD-1) and anti-PD-L1) have been revolutionized to improve immune responses. However, their therapeutic efficacy is limited to 15%–20% of the overall objective response rate. Moreover, PD-L1 is secreted from tumor cells, which can interrupt antibody-mediated immune reactions in the tumor microenvironment. METHODS: We developed poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) encapsulating PD-L1 small interfering RNA (siRNA) and PD-1 siRNA, as a delivery platform to silence immune checkpoints. This study used the TC-1 and EG7 tumor models to determine the potential therapeutic efficacy of the PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs, on administration twice per week for 4 weeks. Moreover, we observed combination effect of PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs using TC-1 and EG7 tumor-bearing mouse models. RESULTS: PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs boosted the host immune reaction by restoring CD8(+) T cell function and promoting cytotoxic CD8(+) T cell responses. We demonstrated that the combination of NP-based therapeutic vaccine and PLGA (siRNA)-NPs resulted in significant inhibition of tumor growth compared with the control and antibody-based treatments (p<0.001). The proposed system significantly inhibited tumor growth compared with the antibody-based approaches. CONCLUSION: Our findings suggest a potential combination approach for cancer immunotherapy using PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs as novel immune checkpoint silencing agents. BMJ Publishing Group 2022-02-28 /pmc/articles/PMC8886443/ /pubmed/35228265 http://dx.doi.org/10.1136/jitc-2021-003928 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Basic Tumor Immunology
Won, Ji Eun
Byeon, Youngseon
Wi, Tae In
Lee, Chan Mi
Lee, Ju Hyeong
Kang, Tae Heung
Lee, Jeong-Won
Lee, YoungJoo
Park, Yeong-Min
Han, Hee Dong
Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title_full Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title_fullStr Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title_full_unstemmed Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title_short Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
title_sort immune checkpoint silencing using rnai-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886443/
https://www.ncbi.nlm.nih.gov/pubmed/35228265
http://dx.doi.org/10.1136/jitc-2021-003928
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