Immunogenicity of somatic mutations in human gastrointestinal cancers

Science. 2015 Dec 11;350(6266):1387-90. doi: 10.1126/science.aad1253. Epub 2015 Oct 29.


It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4(+) and/or CD8(+) T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen-C*08:02-restricted T cell receptor from CD8(+) TILs that targeted the KRAS(G12D) hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Female
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Neoplasms / immunology*
  • Gastrointestinal Neoplasms / therapy
  • HLA-C Antigens / genetics
  • HLA-C Antigens / immunology
  • Humans
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology
  • Immunotherapy / methods
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Middle Aged
  • Mutation
  • Precision Medicine / methods
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins p21(ras)
  • Receptors, Antigen, T-Cell / immunology
  • ras Proteins / genetics
  • ras Proteins / immunology


  • HLA-C Antigens
  • HLA-C*08 antigen
  • Immunodominant Epitopes
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins