Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers

Schwitalle, Yvette; Kloor, Matthias; Eiermann, Susanne; Linnebacher, Michael; Kienle, Peter; Knaebel, H. P.; Tariverdian, Mirjam; Benner, Axel; Doeberitz, Magnus von Knebel

doi:10.1053/j.gastro.2008.01.015

Cited by 325 publications

(312 citation statements)

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“…A histological difference between sporadic and HNPCC-associated cancers is the presence of dense lymphocytic infiltrates in the tumour micromilieu. 22 Schwitalle et al 32,33 recently showed that frameshift-induced neopeptides in HNPCC may induce this characteristic immune response. We therefore speculate that TGF-b1-mediated interactions with myofibroblast-like stromal fibroblasts are altered in the presence of the immune response in HNPCC.…”

Section: Discussionmentioning

confidence: 99%

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-b1 ligand and a-SMA. Myofibroblasts at the tumour invasion front co-expressed a-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-b1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-b1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-b. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-b1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas. Four and a half LIM domain protein-2 (FHL2) was first identified as a protein differentially expressed in human myoblasts and rhabdomyosarcoma cells, and thus named DRAL (downregulated in rhabdomyosarcoma LIM protein 1 ). FHL2 is a LIM-only protein with four complete and one N-terminal half LIM domains that mediate protein-protein interactions. 2 FHL2 associates with integrin receptors to form focal adhesion contacts and binds signal transducers such as b-catenin. 3-5 Triggered by lipid-induced signalling, such as sphingosine-1-phosphate, FHL2 translocates into the nucleus where it binds several transcription factors including serum response factor, AP1 and androgen receptor and functions as a coactivator or a corepressor to modulate gene expression. [6][7][8] We showed previously that FHL2 is strongly upregulated in mesenchymal cells of wounded skin, and demonstrated a function of FHL2 in myofibroblasts regulating their migration and contraction during cutaneous wound healing. 9 Furthermore, FHL2 is critically involved in matrix assembly allowing migration of cells into the wound area. 10 Analogous to wound healing invasive carcinomas generate a specialised tumour stroma and de...

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Section: Discussionmentioning

confidence: 99%

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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“…It is also noteworthy that the ASTE1/HT001 frameshift mutation has been shown to result in the appearance of neoantigens, which could be recognized by specific T cells, and that tumor-infiltrating lymphocytes isolated from Lynch tumors specifically recognized corresponding frameshift peptides and killed colorectal cancer cells with microsatellite instability in vitro. 20 Nevertheless, the ultimate proof of the specific immune response against the particular putative neoantigens that we characterized remains to be established.…”

Section: Discussionmentioning

confidence: 99%

“…20 A recent finding was the correlation between pronounced lymphocytic infiltration and overexpression of cytotoxic T-cell markers in tumors with microsatellite instability, suggesting that neoantigens in microsatellite-unstable colorectal cancers may elicit a more potent T-cell response than the one found in microsatellite-stable colorectal cancers. 21 Indeed, although numerous studies have previously reported the mutation rate of specific targets in colorectal cancers with microsatellite instability, in contrast, only in a few reports a systematic simultaneous molecular profiling of the different microsatellite instability targets that have been identified over the last 10 years was performed.…”

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confidence: 99%

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

et al. 2009

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Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3 þ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.

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“…In contrast, pronounced lymphocytic infiltration is marked in high-graded microsatellite instable (MSI-H) CRC and might explain the better clinical outcome in these patients [64]. It has been postulated that MSI-H CRC are more immunogenic than microsatellite stable (MSS) tumors because of the generation of a large number of abnormal peptides by frameshift mutations [49,[65][66][67][68][69][70]. However, in the analysis of Chiba et al [52] there was no significant increase in the number of CD8 + IEL in cases with MSI.…”

Section: Tumor-infiltrating Lymphocytes and Msi-statusmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers

Cited by 325 publications

References 24 publications

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

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