Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy
IntroductionPost translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon M...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1066185/full |
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| author | Victoria Anne Brentville Peter Symonds JiaXin Chua Anne Skinner Ian Daniels Katherine Wendy Cook Sasa Koncarevic Roxana Martinez-Pinna Sabaria Shah Ruhul Hasan Choudhury Poonam Vaghela Daisy Weston Abdullah Al-Omari James Davis Lindy G. Durrant Lindy G. Durrant |
| author_facet | Victoria Anne Brentville Peter Symonds JiaXin Chua Anne Skinner Ian Daniels Katherine Wendy Cook Sasa Koncarevic Roxana Martinez-Pinna Sabaria Shah Ruhul Hasan Choudhury Poonam Vaghela Daisy Weston Abdullah Al-Omari James Davis Lindy G. Durrant Lindy G. Durrant |
| author_sort | Victoria Anne Brentville |
| collection | DOAJ |
| description | IntroductionPost translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy.MethodsA citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model.ResultsWe show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide.ConclusionWe propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach. |
| first_indexed | 2024-04-12T03:42:55Z |
| format | Article |
| id | doaj.art-28d852b1f8be4f17aed578ed2a659ca7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T03:42:55Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-28d852b1f8be4f17aed578ed2a659ca72022-12-22T03:49:14ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10661851066185Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapyVictoria Anne Brentville0Peter Symonds1JiaXin Chua2Anne Skinner3Ian Daniels4Katherine Wendy Cook5Sasa Koncarevic6Roxana Martinez-Pinna7Sabaria Shah8Ruhul Hasan Choudhury9Poonam Vaghela10Daisy Weston11Abdullah Al-Omari12James Davis13Lindy G. Durrant14Lindy G. Durrant15Scancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomProteome Sciences R & D GmbH & Co.KG, Frankfurt-am-Main, GermanyProteome Sciences R & D GmbH & Co.KG, Frankfurt-am-Main, GermanyScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United KingdomScancell Limited, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United KingdomIntroductionPost translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy.MethodsA citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model.ResultsWe show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide.ConclusionWe propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1066185/fullcitrullinationcancerMHC-IIpost-translation modificationsGRP78 |
| spellingShingle | Victoria Anne Brentville Peter Symonds JiaXin Chua Anne Skinner Ian Daniels Katherine Wendy Cook Sasa Koncarevic Roxana Martinez-Pinna Sabaria Shah Ruhul Hasan Choudhury Poonam Vaghela Daisy Weston Abdullah Al-Omari James Davis Lindy G. Durrant Lindy G. Durrant Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy Frontiers in Immunology citrullination cancer MHC-II post-translation modifications GRP78 |
| title | Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy |
| title_full | Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy |
| title_fullStr | Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy |
| title_full_unstemmed | Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy |
| title_short | Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy |
| title_sort | citrullinated glucose regulated protein 78 is a candidate target for melanoma immunotherapy |
| topic | citrullination cancer MHC-II post-translation modifications GRP78 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1066185/full |
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