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

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

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  • 1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Group Cancer Early Detection, German Cancer Research Center (DKFZ), Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.

Abstract

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.

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PMID:
18395080
[PubMed - indexed for MEDLINE]
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