Indicators of responsiveness to immune checkpoint inhibitors

Abstract Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma...

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Autores principales:	Bradley D. Shields, Fade Mahmoud, Erin M. Taylor, Stephanie D. Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel G. Mackintosh, Ricky D. Edmondson, Sara Shalin, Alan J. Tackett
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cef50263e016446d94ea892a09c098c1
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spelling	oai:doaj.org-article:cef50263e016446d94ea892a09c098c12021-12-02T12:31:49ZIndicators of responsiveness to immune checkpoint inhibitors10.1038/s41598-017-01000-22045-2322https://doaj.org/article/cef50263e016446d94ea892a09c098c12017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01000-2https://doaj.org/toc/2045-2322Abstract Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to checkpoint blockade, which revealed biological signatures that can stratify patients as responders or non-responders. Furthermore, our findings provide evidence of mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Our results have implications for checkpoint inhibitor therapy as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.Bradley D. ShieldsFade MahmoudErin M. TaylorStephanie D. ByrumDeepanwita SenguptaBrian KossGiulia BaldiniSeth RansomKyle ClineSamuel G. MackintoshRicky D. EdmondsonSara ShalinAlan J. TackettNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bradley D. Shields Fade Mahmoud Erin M. Taylor Stephanie D. Byrum Deepanwita Sengupta Brian Koss Giulia Baldini Seth Ransom Kyle Cline Samuel G. Mackintosh Ricky D. Edmondson Sara Shalin Alan J. Tackett Indicators of responsiveness to immune checkpoint inhibitors
description	Abstract Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to checkpoint blockade, which revealed biological signatures that can stratify patients as responders or non-responders. Furthermore, our findings provide evidence of mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Our results have implications for checkpoint inhibitor therapy as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.
format	article
author	Bradley D. Shields Fade Mahmoud Erin M. Taylor Stephanie D. Byrum Deepanwita Sengupta Brian Koss Giulia Baldini Seth Ransom Kyle Cline Samuel G. Mackintosh Ricky D. Edmondson Sara Shalin Alan J. Tackett
author_facet	Bradley D. Shields Fade Mahmoud Erin M. Taylor Stephanie D. Byrum Deepanwita Sengupta Brian Koss Giulia Baldini Seth Ransom Kyle Cline Samuel G. Mackintosh Ricky D. Edmondson Sara Shalin Alan J. Tackett
author_sort	Bradley D. Shields
title	Indicators of responsiveness to immune checkpoint inhibitors
title_short	Indicators of responsiveness to immune checkpoint inhibitors
title_full	Indicators of responsiveness to immune checkpoint inhibitors
title_fullStr	Indicators of responsiveness to immune checkpoint inhibitors
title_full_unstemmed	Indicators of responsiveness to immune checkpoint inhibitors
title_sort	indicators of responsiveness to immune checkpoint inhibitors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/cef50263e016446d94ea892a09c098c1
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Indicators of responsiveness to immune checkpoint inhibitors

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