Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers

Gastroenterology. 2008 Apr;134(4):988-97. doi: 10.1053/j.gastro.2008.01.015. Epub 2008 Jan 11.


Background & aims: Colorectal cancers (CRC) associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome display high-level microsatellite instability (MSI-H) as a consequence of mismatch repair deficiency. HNPCC-associated CRC frequently show features of a pronounced immune response, most likely resulting from the MSI-induced generation of novel tumor-specific carboxy-terminal frameshift peptides (FSPs). However, the role of FSP-specific immune surveillance mechanisms in HNPCC are unknown at present.

Methods: The efficacy of tumor-infiltrating T cells isolated from MSI-H CRCs (n = 3) was examined by in vitro killing assays. FSP-specific T-cell responses were measured by enzyme-linked immunospot in the peripheral blood from patients with MSI-H CRC (n = 32), healthy HNPCC mutation carriers (n = 16), patients with microsatellite stable (MSS) CRC (n = 17), and healthy donors (n = 22).

Results: Tumor-infiltrating T cells isolated from MSI-H CRCs specifically recognized MSI-induced FSPs and showed cytotoxic activity against MSI-H but not MSS CRC cells. FSP-specific T-cell responses were detected in the majority of peripheral blood samples from patients with MSI-H but not MSS CRC. Interestingly, FSP-specific T-cell reactivity was already detectable in the peripheral blood of healthy HNPCC family members with germline mutations but without history of tumor development.

Conclusions: These data suggest that FSPs presented by DNA mismatch repair-deficient CRC cells are effectively recognized by the patient's immune system and may explain the characteristic clinicopathologic features of HNPCC-associated but also sporadic MSI-H CRCs. These observations are of high relevance for the development of FSP-based vaccination approaches, particularly for the preventive application in HNPCC mutation carriers.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / immunology*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / metabolism
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • Enzyme-Linked Immunosorbent Assay
  • Heterozygote
  • Humans
  • Immunity, Cellular / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mass Spectrometry
  • Microsatellite Instability*
  • Neoplasm Proteins / genetics*
  • Prognosis
  • T-Lymphocyte Subsets / immunology*


  • Antigens, CD
  • DNA, Neoplasm
  • Neoplasm Proteins