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Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression

BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune...

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Autores principales: Hwang, Bin-Jin, Tsao, Li-Chung, Acharya, Chaitanya R, Trotter, Timothy, Agarwal, Pankaj, Wei, Junping, Wang, Tao, Yang, Xiao-Yi, Lei, Gangjun, Osada, Takuya, Lyerly, Herbert Kim, Morse, Michael A, Hartman, Zachary Conrad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971789/
https://www.ncbi.nlm.nih.gov/pubmed/35361727
http://dx.doi.org/10.1136/jitc-2021-003721
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author Hwang, Bin-Jin
Tsao, Li-Chung
Acharya, Chaitanya R
Trotter, Timothy
Agarwal, Pankaj
Wei, Junping
Wang, Tao
Yang, Xiao-Yi
Lei, Gangjun
Osada, Takuya
Lyerly, Herbert Kim
Morse, Michael A
Hartman, Zachary Conrad
author_facet Hwang, Bin-Jin
Tsao, Li-Chung
Acharya, Chaitanya R
Trotter, Timothy
Agarwal, Pankaj
Wei, Junping
Wang, Tao
Yang, Xiao-Yi
Lei, Gangjun
Osada, Takuya
Lyerly, Herbert Kim
Morse, Michael A
Hartman, Zachary Conrad
author_sort Hwang, Bin-Jin
collection PubMed
description BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. METHODS: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. RESULTS: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. CONCLUSION: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.
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spelling pubmed-89717892022-04-20 Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression Hwang, Bin-Jin Tsao, Li-Chung Acharya, Chaitanya R Trotter, Timothy Agarwal, Pankaj Wei, Junping Wang, Tao Yang, Xiao-Yi Lei, Gangjun Osada, Takuya Lyerly, Herbert Kim Morse, Michael A Hartman, Zachary Conrad J Immunother Cancer Oncolytic and Local Immunotherapy BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. METHODS: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. RESULTS: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. CONCLUSION: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers. BMJ Publishing Group 2022-03-30 /pmc/articles/PMC8971789/ /pubmed/35361727 http://dx.doi.org/10.1136/jitc-2021-003721 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Oncolytic and Local Immunotherapy
Hwang, Bin-Jin
Tsao, Li-Chung
Acharya, Chaitanya R
Trotter, Timothy
Agarwal, Pankaj
Wei, Junping
Wang, Tao
Yang, Xiao-Yi
Lei, Gangjun
Osada, Takuya
Lyerly, Herbert Kim
Morse, Michael A
Hartman, Zachary Conrad
Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title_full Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title_fullStr Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title_full_unstemmed Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title_short Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
title_sort sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through mavs overexpression
topic Oncolytic and Local Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971789/
https://www.ncbi.nlm.nih.gov/pubmed/35361727
http://dx.doi.org/10.1136/jitc-2021-003721
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