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Cancer neoepitopes for immunotherapy: discordance between tumor-infiltrating T cell reactivity and tumor MHC peptidome display

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor-antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A*02:01 epitope prediction from tumor cell lines from two HLA-A2 positive melanoma patients whose TIL displayed strong tum...

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Main Authors: Wickström, Stina L. (Author) , Lövgren, Tanja (Author) , Volkmar, Michael (Author) , Reinhold, Bruce (Author) , Duke-Cohan, Jonathan S. (Author) , Hartmann, Laura (Author) , Rebmann, Janina (Author) , Mueller, Anja (Author) , Melief, Jeroen (Author) , Maas, Roeltje (Author) , Ligtenberg, Maarten (Author) , Hansson, Johan (Author) , Offringa, Rienk (Author) , Seliger, Barbara (Author) , Poschke, Isabel (Author) , Reinherz, Ellis L. (Author) , Kiessling, Rolf (Author)
Format: Article (Journal)
Language:English
Published: 11 December 2019
In: Frontiers in immunology
Year: 2019, Volume: 10
ISSN:1664-3224
DOI:10.3389/fimmu.2019.02766
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.3389/fimmu.2019.02766
Verlag: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02766/full
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Author Notes:Stina L. Wickström, Tanja Lövgren, Michael Volkmar, Bruce Reinhold, Jonathan S. Duke-Cohan, Laura Hartmann, Janina Rebmann, Anja Mueller, Jeroen Melief, Roeltje Maas, Maarten Ligtenberg, Johan Hansson, Rienk Offringa, Barbara Seliger, Isabel Poschke, Ellis L. Reinherz and Rolf Kiessling
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Summary:Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor-antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A*02:01 epitope prediction from tumor cell lines from two HLA-A2 positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC -I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS-screening detected 3/181 neoepitopes on tumor MHC I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope-specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-γ treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC-presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.
Item Description:Gesehen am 24.01.2020
Physical Description:Online Resource
ISSN:1664-3224
DOI:10.3389/fimmu.2019.02766

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