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hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC
BACKGROUND: Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450042/ https://www.ncbi.nlm.nih.gov/pubmed/37612043 http://dx.doi.org/10.1136/jitc-2023-006913 |
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author | Trono, Paola Tocci, Annalisa Palermo, Belinda Di Carlo, Anna D'Ambrosio, Lorenzo D'Andrea, Daniel Di Modugno, Francesca De Nicola, Francesca Goeman, Frauke Corleone, Giacomo Warren, Sarah Paolini, Francesca Panetta, Mariangela Sperduti, Isabella Baldari, Silvia Visca, Paolo Carpano, Silvia Cappuzzo, Federico Russo, Vincenzo Tripodo, Claudio Zucali, Paolo Gregorc, Vanesa Marchesi, Federica Nistico, Paola |
author_facet | Trono, Paola Tocci, Annalisa Palermo, Belinda Di Carlo, Anna D'Ambrosio, Lorenzo D'Andrea, Daniel Di Modugno, Francesca De Nicola, Francesca Goeman, Frauke Corleone, Giacomo Warren, Sarah Paolini, Francesca Panetta, Mariangela Sperduti, Isabella Baldari, Silvia Visca, Paolo Carpano, Silvia Cappuzzo, Federico Russo, Vincenzo Tripodo, Claudio Zucali, Paolo Gregorc, Vanesa Marchesi, Federica Nistico, Paola |
author_sort | Trono, Paola |
collection | PubMed |
description | BACKGROUND: Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA(11a) isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA(11a) downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA(11a) downregulation. METHODS: Effects of hMENA(11a) downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort. RESULTS: Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA(11a) induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA(11a), high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy. CONCLUSIONS: Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA(11a) in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC. |
format | Online Article Text |
id | pubmed-10450042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-104500422023-08-26 hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC Trono, Paola Tocci, Annalisa Palermo, Belinda Di Carlo, Anna D'Ambrosio, Lorenzo D'Andrea, Daniel Di Modugno, Francesca De Nicola, Francesca Goeman, Frauke Corleone, Giacomo Warren, Sarah Paolini, Francesca Panetta, Mariangela Sperduti, Isabella Baldari, Silvia Visca, Paolo Carpano, Silvia Cappuzzo, Federico Russo, Vincenzo Tripodo, Claudio Zucali, Paolo Gregorc, Vanesa Marchesi, Federica Nistico, Paola J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA(11a) isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA(11a) downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA(11a) downregulation. METHODS: Effects of hMENA(11a) downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort. RESULTS: Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA(11a) induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA(11a), high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy. CONCLUSIONS: Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA(11a) in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC. BMJ Publishing Group 2023-08-23 /pmc/articles/PMC10450042/ /pubmed/37612043 http://dx.doi.org/10.1136/jitc-2023-006913 Text en © Author(s) (or their employer(s)) 2023. 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 | Immunotherapy Biomarkers Trono, Paola Tocci, Annalisa Palermo, Belinda Di Carlo, Anna D'Ambrosio, Lorenzo D'Andrea, Daniel Di Modugno, Francesca De Nicola, Francesca Goeman, Frauke Corleone, Giacomo Warren, Sarah Paolini, Francesca Panetta, Mariangela Sperduti, Isabella Baldari, Silvia Visca, Paolo Carpano, Silvia Cappuzzo, Federico Russo, Vincenzo Tripodo, Claudio Zucali, Paolo Gregorc, Vanesa Marchesi, Federica Nistico, Paola hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title | hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title_full | hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title_fullStr | hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title_full_unstemmed | hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title_short | hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC |
title_sort | hmena isoforms regulate cancer intrinsic type i ifn signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in nsclc |
topic | Immunotherapy Biomarkers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450042/ https://www.ncbi.nlm.nih.gov/pubmed/37612043 http://dx.doi.org/10.1136/jitc-2023-006913 |
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