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Elife. 2018 Nov 30;7. pii: e41090. doi: 10.7554/eLife.41090.

Rejection of immunogenic tumor clones is limited by clonal fraction.

Author information

1
Tri-Institutional MD-PhD Program, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Weill Cornell Medical College, New York, United States.
2
Weill Cornell Medicine, New York, United States.
3
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
4
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States.
5
Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, United States.
6
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
#
Contributed equally

Abstract

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.

KEYWORDS:

cancer biology; cancer immunology; genetic heterogeneity; mouse; tumor antigens; tumor evolution; tumor resistance to immune response

Comment in

PMID:
30499773
PMCID:
PMC6269121
DOI:
10.7554/eLife.41090
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

RG Memorial Sloan Kettering Cancer Center has filed for intellectual property protection for the inventions of this author in relation to the PresentER method. AC Memorial Sloan Kettering Cancer Center has filed for intellectual property protection for the inventions of this author in relation to TCR mimic antibodies. HJ, KD, AH, AS No competing interests declared, DS Memorial Sloan Kettering Cancer Center has filed for intellectual property protection for the inventions of this author in relation to the PresentER method and TCR mimic antibodies. DAS is also a board member of, or consultant to, and/or owns equity in SLS, IOVA, PFE, and Eureka therapeutics that work in the immunotherapy field.

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