Loss of HLA-A,B,C allele products and lymphocyte function-associated antigen 3 in colorectal neoplasia.

Smith, Mark E.; Marsh, Steven G.E.; Bodmer, Julia G.; Gelsthorpe, K.; Bodmer, Walter F.

doi:10.1073/pnas.86.14.5557

Cited by 104 publications

(57 citation statements)

References 30 publications

(24 reference statements)

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“…Our observed frequency of alterations in HLA-I is in agreement with other studies and suggests that our study cohort is comparable with other reported populations (Cordon et al, 1991;Durrant et al, 1987;Kaklamanis et al, 1992;Lopez-Nevot et al, 1989;Moller et al, 1991aMoller et al, , 1991bMoore et al, 1986;Smith et al, 1989;Stein et al, 1988;van den Ingh et al, 1987). The improved prognosis for patients with tumors that had down-regulated HLA-I, and HLA-A in particular, is a novel finding and argues against the importance of T-cell-mediated immune surveillance.…”

Section: Discussionsupporting

confidence: 82%

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Menon

Morreau

Tollenaar

et al. 2002

Laboratory Investigation

117

104

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SUMMARY:To evaluate the prognostic impact of human leukocyte antigen class I (HLA-I) expression on immune surveillance in colorectal cancer, we studied 88 curatively resected tumors for HLA-A and HLA-B/C expression and correlated these data to clinical and histopathological parameters. HLA-A was normal (all tumor cells had HLA expression) in 32%, reduced (HLA-negative and -positive tumor cells coexisted) in 56%, or absent (no tumor cells expressed HLA) in 12% of evaluable cases. HLA-B/C was normal in 47%, reduced in 47%, and absent in 7% of the cases. Considering both markers, total HLA-I expression was normal in 27%, reduced in 63%, absent in 7%, and could not be evaluated in 3% of the cases due to absent HLA-A expression in tumor and normal cells. Down-regulation of HLA-A expression significantly correlated with a lower tumor stage (p ϭ 0.005), mucinous tumors (p ϭ 0.05), a lower incidence of recurrences (p ϭ 0.03), and a longer disease-free survival (p ϭ 0.02). Down-regulation of HLA-B/C expression correlated with a lower tumor stage (p Ͻ 0.001) and a longer disease-free survival (p ϭ 0.04). In multivariate analysis, HLA-A down-regulation was the only prognostic factor correlated with a longer disease-free survival (p ϭ 0.02). Six tumors were negative for HLA-A and -B/C and did not recur during follow-up. Therefore, we analyzed microsatellite instability (MSI) in these cases. Three of these six tumors indeed showed down-regulation of MLH-1, MSH-2, or MSH-6, indicating a MSI-high phenotype. Beta-2-microglobulin protein expression was lost in five of six of the HLA-I-negative cases, but frame shift mutations in three repetitive sequences in ␤2-microglobulin were absent. In contrast, loss of MLH-1, MSH-2, and MSH-6-protein expression was only observed in two of nine matched controls with reduced or normal HLA-A and -B/C expression. Our data showed that HLA-I was down-regulated in 72% of colorectal cancers and provided independent prognostic information for a longer disease-free survival. The better prognosis may be caused by elimination of HLA-negative cells by natural killer cells or by an attenuated tumor aggressiveness, as is seen in tumors with a MSI-high phenotype. (Lab Invest 2002, 82:1725-1733.

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Section: Discussionsupporting

confidence: 82%

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Menon

Morreau

Tollenaar

et al. 2002

Laboratory Investigation

117

104

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“…The selective loss of expression of individual HLA molecules on tumor cells has been described (13,41). In this study we have identified two cell lines (LS 174T and LS 411), in which loss of expression of HLA-A2 has occurred.…”

Section: Discussionmentioning

confidence: 86%

“…Surface expression of this complex controls the recognition of a cell by antigen-specific cytotoxic T lymphocytes (2,3) and has been implicated in the rejection of intracellular parasites (4,5), tumors (6,7), and tissue allografts (8). Loss of expression of HLA molecules has been described on a wide variety of tumor types (9)(10)(11)(12)(13) and has been argued as presenting a mechanism whereby a tumor cell can escape from immune surveillance by cytotoxic T lymphocytes (14,15). To better understand the control of HLA expression on tumor cells, we have established a DNA-based method for tissue typing the HLA-A locus by a one-step PCR from genomic DNA.…”

mentioning

confidence: 99%

Tissue typing the HLA-A locus from genomic DNA by sequence-specific PCR: comparison of HLA genotype and surface expression on colorectal tumor cell lines.

Browning

Krausa

Rowan

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

164

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A system devised for tissue typing the HLA-A locus by PCR from genomic DNA has been used to investigate abnormalities of HLA expression in a panel of 30 colorectal tumor cell lines, by comparing the HLA-A locus genotype with surface expression of HLA. Three cell lines showed complete lack of HLA expression associated with failure to express .82-microglobulin. In two other cell lines, loss of expression of HLA-A2 was observed, in spite of the presence of the gene in genomic DNA. Eleven cell lines gave a single HLA-A locus specificity on PCR typing. In one of these cell lines we have demonstrated the loss of an HLA-A locus gene in the tumor cell by comparison with DNA from a lymphoblastoid B-cell line derived from the same patient. These data indicate that at least three independent mechanisms were involved in the loss of HLA expression on the colorectal tumor cell lines.

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“…In vitro, both CD58 and CD59 antibody alone were shown to reduce the CD2-dependent response of a murine T-cell clone expressing human CD2 (Hahn et al, 1992). It is thus conceivable that presence of CD59 on the cell surface might compensate a reduction or loss of LFA-3 (CD58) which has been reported to occur in some colorectal carcinomas (Smith et al, 1989;Koretz et al, 1991). In view of the novel functions attributed to CD55 and CD59, presence of CD55 and absence of CD59 might contribute to resistance of a tumour cell to cell-mediated cytotoxicity unrestricted and restricted, respectively, by the major histocompatibility complex (Browning & Bodmer, 1992;Moller & Hammerling, 1992).…”

Section: Discussionmentioning

confidence: 99%

Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium

Koretz

Brüderlein²,

Henne³

et al. 1993

Br J Cancer

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SummaryCD59 (protectin) and CD46 (membrane cofactor protein, MCP) are membrane-bound complement regulator proteins which inhibit complement-mediated cytolysis of autologous cells. CD59, a phosphatidyl-inositol-anchored glycoprotein, inhibits the formation of the terminal membrane attack complex (MAC) of complement and was found to be a second ligand for CD2 contributing to T-cell activation. In 20 colorectal normal mucosa samples, in ten adenomas, 71 carcinomas and in ten liver metastases derived thereof, CD59 was inconsistently expressed in the epithelial compartment. In carcinomas CD59 expression in the whole neoplastic compartment was more often found in well-and moderately differentiated tumours. By contrast, focal expression or even complete lack of CD59 was more often found in poorly differentiated tumours (P = 0.021). In addition, carcinomas without metastases at the time of operation (Dukes A/B) more often expressed CD59 in the entire neoplastic population compared to those carcinomas which had already metastasised (P = 0.018). There was no correlation between the mode of CD59 expression in colorectal carcinomas and the tumour type or location. CD46 has C3b/C4b binding and factor-I dependent cofactor activity and is broadly expressed in various cells and tissues. In the epithelial compartment of normal colorectal mucosa, of all adenomas, carcinomas and their liver metastases, CD46 was expressed throughout the epithelial compartment.Since CD46 was consistently expressed in colorectal carcinomas the low expression or even lack of CD59 in a subset of tumours might not lead to critical complement-mediated attack of CD59-negative tumour cells. Regarding CD59 as a natural T-cell ligand involved in cognate T-cell -target-cell interaction, however, loss of CD59 might well be a selection advantage, provided that tumour antigen-mediated T-cell toxicity in colorectal carcinoma exists.Membrane-bound regulatory proteins protect autologous cells from complement mediated cytotoxicity when fragments of the complement cascade are deposited on host cells which are not the desired target (Davitz, 1986). These proteins regulate the coordinating points in the classic and alternative pathways, the formation of the C3 convertases and the assembly of the terminal membrane attack complex (MAC) (Kinoshita, 1991). One of these proteins which aids in regulating the latter is protectin or CD59 (Hadam, 1989a), an 18-20 kD phosphatidyl-inositol anchored glycoprotein (Meri et al., 1990;Ratnoff et al., 1992). CD59 restricts homologous lysis by binding to the C8 and C9 molecules during the MAC formation, thus disturbing the C8: C9 ratio in the MAC complex (Meri et al., 1990;Lachmann, 1991 Asghar, 1992) where it functions as a second ligand for CD2 (Hahn et al., 1992). One protein which helps regulate the formation of the C3 convertases on autologous cells (Kinoshita, 1991) and the C5 convertase of the alternative complement pathway (Seya et al., 1991) is the 45-70 kD membrane cofactor protein (MCP) (Lublin & Atkinson, 1989) or CD46 (H...

show abstract

Loss of HLA-A,B,C allele products and lymphocyte function-associated antigen 3 in colorectal neoplasia.

Cited by 104 publications

References 30 publications

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Tissue typing the HLA-A locus from genomic DNA by sequence-specific PCR: comparison of HLA genotype and surface expression on colorectal tumor cell lines.

Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium

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