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Citrullinated α-enolase is an effective target for anti-cancer immunity

Targeting post-translationally modified epitopes may provide a new strategy for generating tumor specific immune responses. Citrullination is the post-translational modification of arginine to citrulline catalyzed by peptidylarginine deaminase (PAD) enzymes. Presentation of citrullinated peptides on...

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Autores principales: Cook, Katherine, Daniels, Ian, Symonds, Peter, Pitt, Tracy, Gijon, Mohamed, Xue, Wei, Metheringham, Rachael, Durrant, Lindy, Brentville, Victoria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749660/
https://www.ncbi.nlm.nih.gov/pubmed/29308319
http://dx.doi.org/10.1080/2162402X.2017.1390642
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author Cook, Katherine
Daniels, Ian
Symonds, Peter
Pitt, Tracy
Gijon, Mohamed
Xue, Wei
Metheringham, Rachael
Durrant, Lindy
Brentville, Victoria
author_facet Cook, Katherine
Daniels, Ian
Symonds, Peter
Pitt, Tracy
Gijon, Mohamed
Xue, Wei
Metheringham, Rachael
Durrant, Lindy
Brentville, Victoria
author_sort Cook, Katherine
collection PubMed
description Targeting post-translationally modified epitopes may provide a new strategy for generating tumor specific immune responses. Citrullination is the post-translational modification of arginine to citrulline catalyzed by peptidylarginine deaminase (PAD) enzymes. Presentation of citrullinated peptides on MHC-II has been associated with autophagy. Tumors upregulate autophagy and present citrullinated peptides in response to stresses including nutrient deprivation, oxygen deprivation, redox stress and DNA damage, making them good targets for immune attack. The ubiquitous glycolytic enzyme α-enolase (ENO1) is often citrullinated and degraded during autophagy. Immunization of mice with two citrullinated ENO1 peptides (ENO1 241–260cit(253) or 11–25cit(15)) induced strong Th1 responses that recognize the post-translationally modified, but not the wild type unmodified epitope. ENO1 11–25cit(15) induced tumor therapy of melanoma cells in C57Bl/6 (B16F1 50% survival p = 0.0026) and ENO1 241–260cit(253) in HLA-DR4 transgenic mice (B16-DR4 50% survival p = 0.0048). In addition, ENO1 241–260cit(253) induced therapy of pancreatic (Pan02-DR4 50% survival p = 0.0076) and lung (LLC/2-DR4 40% survival p = 0.0142) tumors in HLA-DR4 transgenic mice. The unmodified epitope induced no anti-tumor response. Minimal regression of class II negative B16 or LLC/2 tumor was seen, confirming direct recognition of MHC-II was required. Most tumors only express MHC-II in the presence of IFNγ; an IFNγ inducible model showed strong responses, with rejection of tumors in up to 90% of animals (p = 0.0001). In humans, a repertoire to ENO1 241–260cit(253) was observed in healthy donors. This response was CD4 mediated and seen in people with a variety of HLA types suggesting a broad application for this vaccine in human cancer therapy.
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spelling pubmed-57496602018-11-06 Citrullinated α-enolase is an effective target for anti-cancer immunity Cook, Katherine Daniels, Ian Symonds, Peter Pitt, Tracy Gijon, Mohamed Xue, Wei Metheringham, Rachael Durrant, Lindy Brentville, Victoria Oncoimmunology Original Research Targeting post-translationally modified epitopes may provide a new strategy for generating tumor specific immune responses. Citrullination is the post-translational modification of arginine to citrulline catalyzed by peptidylarginine deaminase (PAD) enzymes. Presentation of citrullinated peptides on MHC-II has been associated with autophagy. Tumors upregulate autophagy and present citrullinated peptides in response to stresses including nutrient deprivation, oxygen deprivation, redox stress and DNA damage, making them good targets for immune attack. The ubiquitous glycolytic enzyme α-enolase (ENO1) is often citrullinated and degraded during autophagy. Immunization of mice with two citrullinated ENO1 peptides (ENO1 241–260cit(253) or 11–25cit(15)) induced strong Th1 responses that recognize the post-translationally modified, but not the wild type unmodified epitope. ENO1 11–25cit(15) induced tumor therapy of melanoma cells in C57Bl/6 (B16F1 50% survival p = 0.0026) and ENO1 241–260cit(253) in HLA-DR4 transgenic mice (B16-DR4 50% survival p = 0.0048). In addition, ENO1 241–260cit(253) induced therapy of pancreatic (Pan02-DR4 50% survival p = 0.0076) and lung (LLC/2-DR4 40% survival p = 0.0142) tumors in HLA-DR4 transgenic mice. The unmodified epitope induced no anti-tumor response. Minimal regression of class II negative B16 or LLC/2 tumor was seen, confirming direct recognition of MHC-II was required. Most tumors only express MHC-II in the presence of IFNγ; an IFNγ inducible model showed strong responses, with rejection of tumors in up to 90% of animals (p = 0.0001). In humans, a repertoire to ENO1 241–260cit(253) was observed in healthy donors. This response was CD4 mediated and seen in people with a variety of HLA types suggesting a broad application for this vaccine in human cancer therapy. Taylor & Francis 2017-11-06 /pmc/articles/PMC5749660/ /pubmed/29308319 http://dx.doi.org/10.1080/2162402X.2017.1390642 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Original Research
Cook, Katherine
Daniels, Ian
Symonds, Peter
Pitt, Tracy
Gijon, Mohamed
Xue, Wei
Metheringham, Rachael
Durrant, Lindy
Brentville, Victoria
Citrullinated α-enolase is an effective target for anti-cancer immunity
title Citrullinated α-enolase is an effective target for anti-cancer immunity
title_full Citrullinated α-enolase is an effective target for anti-cancer immunity
title_fullStr Citrullinated α-enolase is an effective target for anti-cancer immunity
title_full_unstemmed Citrullinated α-enolase is an effective target for anti-cancer immunity
title_short Citrullinated α-enolase is an effective target for anti-cancer immunity
title_sort citrullinated α-enolase is an effective target for anti-cancer immunity
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749660/
https://www.ncbi.nlm.nih.gov/pubmed/29308319
http://dx.doi.org/10.1080/2162402X.2017.1390642
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