Gejman and Chang et al. developed PresentER — a method of evaluating antigen immunogenicity using libraries of epitope-length peptide minigenes presented on the MHC-I of tumor cells, with each cell displaying a different antigen. Surprisingly, the researchers found that an effective T cell response against an immunogenic peptide is mounted only if the fraction of tumor cells expressing this peptide is high enough, with the critical threshold varying by antigen. This result represents a possible mechanism for immune escape, particularly in very early or heterogeneous tumors where the clonal fraction of each antigen is low.
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.
Author Info: (1) Tri-Institutional MD-PhD Program, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Weill Cornell Medical College, New York, United States. Weill Cornell Medicine
Author Info: (1) Tri-Institutional MD-PhD Program, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Weill Cornell Medical College, New York, United States. Weill Cornell Medicine, New York, United States. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States. (2) Weill Cornell Medicine, New York, United States. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States. (3) Weill Cornell Medicine, New York, United States. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States. (4) Weill Cornell Medicine, New York, United States. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States. (5) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, United States. (6) Weill Cornell Medicine, New York, United States. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States. (7) Weill Cornell Medicine, New York, United States. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
