Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers.
OBJECTIVE
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.
Schwitalle
Yvette
Y
Department 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.
Kloor
Matthias
M
Eiermann
Susanne
S
Linnebacher
Michael
M
Kienle
Peter
P
Knaebel
Hanns Peter
HP
Tariverdian
Mirjam
M
Benner
Axel
A
von Knebel Doeberitz
Magnus
M
D015703:Antigens, CD / Q000276:immunology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D006579:Heterozygote; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D013058:Mass Spectrometry; D053842:Microsatellite Instability; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D015703:Antigens, CD; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins