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• W4244934009 abstract "The manuscript by Schwitalle et al1Schwitalle Y. Kloor M. Eiermann S. et al.Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers.Gastroenterology. 2008; 134: 988-997Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar has initiated a welcome new interest on immune responses against frameshift-induced neopeptides in microsatellite instable (MSI-H [colorectal]) cancer and potential use as vaccine.1Schwitalle Y. Kloor M. Eiermann S. et al.Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers.Gastroenterology. 2008; 134: 988-997Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar Frameshift peptide (FSP)–specific T-cell responses were detected in the peripheral blood from patients with MSI-H colorectal cancer (CRC), healthy hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutation carriers, but not in patients with microsatellite stable (MSS) CRC or healthy donors as measured by interferon-γ enzyme-linked ImmunoSPOT. Notably, when patients responded to FSPs, they generally responded to almost all of the selected FSPs. We recently described a methodology to predict the immunogenicity of frameshift-mutated proteins in vivo,2Speetjens F.M. Lauwen M.M. Franken K.L. et al.Prediction of the immunogenic potential of frame shift mutated antigens in microsatellite instable cancer.Int J Cancer. 2008; 15: 838-845Crossref Scopus (27) Google Scholar which is based on the notion that the activation of tumor-specific T cells requires a productive interaction with dendritic cells that cross-present tumor-derived antigens.3Rock K.L. Shen L. Cross-presentation: underlying mechanisms and role in immune surveillance.Immunol Rev. 2005; 207: 166-183Crossref PubMed Scopus (344) Google Scholar, 4Melief C.J. Mini-review: REGULATION of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming?.Eur J Immunol. 2003; 33: 2645-2654Crossref PubMed Scopus (158) Google Scholar Cross-presentation can only occur when frameshift-mutated proteins accumulate in the cells in which they are synthesized so that enough antigen becomes available to the immune system upon death of the tumor cell. Our test system is composed of a gene-expression system, in which each of the proteins was fused to a short C-terminal polypeptide comprising 2 epitopes that can be readily detected by antibodies and T cells, which made it possible to study the accumulation of frameshift-mutated proteins as well as both direct (by tumor cells) and cross-presentation (by dendritic cells) of frameshift-mutated proteins in major histocompatibility complex class I in an in vivo mouse model. The results from this strategy allow to predict which antigens constitute the best targets for a coordinated immune response by both CD8+ and CD4+ T cells, and consequently the likelihood that tumor-induced immunity will be detectable against these antigens in cancer patients. Of our selection of frameshift-mutated proteins, 4 sequences (TGFβR2-1; TAF1B-1; U79260-1; Caspase5-1) were also tested by Schwitalle et al. Our results indicated that MSI patients may exhibit immune responses against TGFβR2-1 and possibly against TAF1B-1 but not to U79260-1 or Caspase5-1. Accordingly, Schwitalle et al showed that half of the patients with a MSI-H tumor indeed responded to TGFβR2-1 and TAF1B-1. Unexpectedly, T cells isolated from patients with a MSI-H tumor were found to respond more frequently to U79260-1 and Caspase5-1 than we would have anticipated (8/32 and 11/32, respectively). Upon examination of the results presented in Figure 3 of their paper, it is clear that the MSI-H CRC patients and the healthy HNPCC subjects responded differently from the controls. Nevertheless, we noted that (1) when patients responded to FSP, they responded equally well to almost all peptides, with no particular sequence being recognized particularly well; (2) that there is a considerable difference between the 6 replicate wells used to determine the response, and (3) that the strongest responses were found in patients in which also the background response was considerably higher. Although the authors rigorously adjust their results by subtracting the spots of background and standard errors of peptide-specific counts and no peptide control, they are less stringent with respect to their determination of a cutoff point to indicate a “strong” FSP-specific T-cell response (≥2.5 positive T cells per 100,000 peripheral blood mononuclear cells [PBMC]). In view of the background levels and standard deviations observed in the assays performed with patients PBMC, we deem this a rather weak cutoff point, which may explain the high number of detected responses against FSPs (eg, U79260-1 and Caspase 5-1), which are not expected to spontaneously activate a FSP-specific T-cell response in vivo. We would encourage Schwitalle et al to continue their studies in the patients described in this publication in order to clearly define which FSPs form targets in the spontaneous immune response and look forward to the confirmation of their results by other types of assays. Furthermore, we express the hope that a combination of our methodology to predict the in vivo immunogenicity of frameshift-mutated proteins and detection of FSP-specific T-cell responses in patient-derived PBMC or tumor-infiltrating lymphocytes may quickly define which FSPs are useful in vaccine approaches. ReplyGastroenterologyVol. 135Issue 2PreviewMicrosatellite unstable (MSI-H) colorectal cancers (CRC) display strong infiltration by immune cells and display characteristic clinical features, suggesting that the pathogenesis of these tumors is associated with the generation of certain cancer antigens. We recently reported that a group of novel frameshift peptides (FSPs) generated through mutations in coding microsatellites trigger strong immune responses in patients with MSI-H cancers. These data suggest that vaccines may be potent novel modes of treating and presumably also preventing this particular form of cancer. Full-Text PDF" @default.
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• W4244934009 title "Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers" @default.
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