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Rejection of immunogenic tumor clones is limited by clonal fraction

Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand t...

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Autores principales: Gejman, Ron S, Chang, Aaron Y, Jones, Heather F, DiKun, Krysta, Hakimi, Abraham Ari, Schietinger, Andrea, Scheinberg, David A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269121/
https://www.ncbi.nlm.nih.gov/pubmed/30499773
http://dx.doi.org/10.7554/eLife.41090
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author Gejman, Ron S
Chang, Aaron Y
Jones, Heather F
DiKun, Krysta
Hakimi, Abraham Ari
Schietinger, Andrea
Scheinberg, David A
author_facet Gejman, Ron S
Chang, Aaron Y
Jones, Heather F
DiKun, Krysta
Hakimi, Abraham Ari
Schietinger, Andrea
Scheinberg, David A
author_sort Gejman, Ron S
collection PubMed
description Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new ‘PresentER’ antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen (‘clonal fraction’) is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines.
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spelling pubmed-62691212018-12-04 Rejection of immunogenic tumor clones is limited by clonal fraction Gejman, Ron S Chang, Aaron Y Jones, Heather F DiKun, Krysta Hakimi, Abraham Ari Schietinger, Andrea Scheinberg, David A eLife Cancer Biology Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new ‘PresentER’ antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen (‘clonal fraction’) is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines. eLife Sciences Publications, Ltd 2018-11-30 /pmc/articles/PMC6269121/ /pubmed/30499773 http://dx.doi.org/10.7554/eLife.41090 Text en © 2018, Gejman et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Gejman, Ron S
Chang, Aaron Y
Jones, Heather F
DiKun, Krysta
Hakimi, Abraham Ari
Schietinger, Andrea
Scheinberg, David A
Rejection of immunogenic tumor clones is limited by clonal fraction
title Rejection of immunogenic tumor clones is limited by clonal fraction
title_full Rejection of immunogenic tumor clones is limited by clonal fraction
title_fullStr Rejection of immunogenic tumor clones is limited by clonal fraction
title_full_unstemmed Rejection of immunogenic tumor clones is limited by clonal fraction
title_short Rejection of immunogenic tumor clones is limited by clonal fraction
title_sort rejection of immunogenic tumor clones is limited by clonal fraction
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269121/
https://www.ncbi.nlm.nih.gov/pubmed/30499773
http://dx.doi.org/10.7554/eLife.41090
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