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Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

ABSTRACT: While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often not known what antigens are being recognized by T cells, or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from murine leukemia virus, an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet failed to delay tumor growth in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and mimotopes that are highly cross-reactive to the endogenous antigen across multiple individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE196782 | GEO | 2022/02/15

REPOSITORIES: GEO

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Project description:This a model from the article: A dynamical perspective of CTL cross-priming and regulation: implications for cancer immunology. Wodarz D, Jansen VA. Immunol Lett 2003 May 1;86(3):213-27 12706524 , Abstract: Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such as viral infections and tumors. At the same time, they can cause disease when induced inappropriately. Which factors regulate CTL and decide whether they should remain silent or react is open to debate. The phenomenon called cross-priming has received attention in this respect. That is, CTL expansion occurs if antigen is recognized on the surface of professional antigen presenting cells (APCs). This is in contrast to direct presentation where antigen is seen on the surface of the target cells (e.g. infected cells or tumor cells). Here we introduce a mathematical model, which takes the phenomenon of cross-priming into account. We propose a new mechanism of regulation which is implicit in the dynamics of the CTL: According to the model, the ability of a CTL response to become established depends on the ratio of cross-presentation to direct presentation of the antigen. If this ratio is relatively high, CTL responses are likely to become established. If this ratio is relatively low, tolerance is the likely outcome. The behavior of the model includes a parameter region where the outcome depends on the initial conditions. We discuss our results with respect to the idea of self/non-self discrimination and the danger signal hypothesis. We apply the model to study the role of CTL in cancer initiation, cancer evolution/progression, and therapeutic vaccination against cancers. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Wodarz D, Jansen VA. (2003) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

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