Reversion analysis reveals the in vivo immunogenicity of a poorly MHC I-binding cancer neoepitope

Hakimeh Ebrahimi-Nik, Marmar Moussa, Ryan P. Englander, Summit Singhaviranon, Justine Michaux, HuiSong Pak, Hiroko Miyadera, William L. Corwin, Grant L. J. Keller, Adam T. Hagymasi, Tatiana V. Shcheglova, George Coukos, Brian M. Baker, Ion I. Mandoiu, Michal Bassani-Sternberg and Pramod K. Srivastava ()
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Hakimeh Ebrahimi-Nik: University of Connecticut School of Medicine
Marmar Moussa: University of Connecticut School of Medicine
Ryan P. Englander: University of Connecticut School of Medicine
Summit Singhaviranon: University of Connecticut School of Medicine
Justine Michaux: Ludwig Institute for Cancer Research, University of Lausanne
HuiSong Pak: Ludwig Institute for Cancer Research, University of Lausanne
Hiroko Miyadera: Faculty of Medicine, University of Tsukuba
William L. Corwin: University of Connecticut School of Medicine
Grant L. J. Keller: University of Notre Dame
Adam T. Hagymasi: University of Connecticut School of Medicine
Tatiana V. Shcheglova: University of Connecticut School of Medicine
George Coukos: Ludwig Institute for Cancer Research, University of Lausanne
Brian M. Baker: University of Notre Dame
Ion I. Mandoiu: University of Connecticut School of Engineering
Michal Bassani-Sternberg: Ludwig Institute for Cancer Research, University of Lausanne
Pramod K. Srivastava: University of Connecticut School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract High-affinity MHC I-peptide interactions are considered essential for immunogenicity. However, some neo-epitopes with low affinity for MHC I have been reported to elicit CD8 T cell dependent tumor rejection in immunization-challenge studies. Here we show in a mouse model that a neo-epitope that poorly binds to MHC I is able to enhance the immunogenicity of a tumor in the absence of immunization. Fibrosarcoma cells with a naturally occurring mutation are edited to their wild type counterpart; the mutation is then re-introduced in order to obtain a cell line that is genetically identical to the wild type except for the neo-epitope-encoding mutation. Upon transplantation into syngeneic mice, all three cell lines form tumors that are infiltrated with activated T cells. However, lymphocytes from the two tumors that harbor the mutation show significantly stronger transcriptional signatures of cytotoxicity and TCR engagement, and induce greater breadth of TCR reactivity than those of the wild type tumors. Structural modeling of the neo-epitope peptide/MHC I pairs suggests increased hydrophobicity of the neo-epitope surface, consistent with higher TCR reactivity. These results confirm the in vivo immunogenicity of low affinity or ‘non-binding’ epitopes that do not follow the canonical concept of MHC I-peptide recognition.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26646-5

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DOI: 10.1038/s41467-021-26646-5

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