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

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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Schwitalle Y,Kloor M,Eiermann S,Linnebacher M,Kienle P,Knaebel HP,Tariverdian M,Benner A,von Knebel Doeberitz M

doi

10.1053/j.gastro.2008.01.015

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

988-97

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(08)00054-1

journal_volume

134

pub_type

杂志文章,多中心研究

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