Title | Rejection of immunogenic tumor clones is limited by clonal fraction. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Gejman RS, Chang AY, Jones HF, DiKun K, Hakimi AAri, Schietinger A, Scheinberg DA |
Journal | Elife |
Volume | 7 |
Date Published | 2018 11 30 |
ISSN | 2050-084X |
Keywords | Animals, Antigen Presentation, Antigens, Neoplasm, Base Sequence, Bystander Effect, Cell Line, Tumor, Clone Cells, Cytotoxicity, Immunologic, Gene Library, Immunocompetence, Major Histocompatibility Complex, Mice, Inbred C57BL, Neoplasms, Peptides, Receptors for Activated C Kinase, T-Lymphocytes, Vaccination |
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. |
DOI | 10.7554/eLife.41090 |
Alternate Journal | Elife |
PubMed ID | 30499773 |
PubMed Central ID | PMC6269121 |
Grant List | Core Grant P30 CA008748 / CA / NCI NIH HHS / United States R01 CA055349 / CA / NCI NIH HHS / United States T32GM07739 / GM / NIGMS NIH HHS / United States F30 CA200327 / CA / NCI NIH HHS / United States DP2 CA225212 / NH / NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States PO1 CA 55349 and CA23766 / CA / NCI NIH HHS / United States |
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