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

Menon, Anand; Morreau, Hans; Tollenaar, Rob A.E.M.; Alphenaar, E; Puijenbroek, Marjo van; Putter, Hein; Rhijn, Connie M. Janssen-van; Velde, Cornelis J.H. van de; Fleuren, Gert Jan; Kuppen, Peter J. K.

doi:10.1097/01.lab.0000043124.75633.ed

Cited by 117 publications

(113 citation statements)

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“…In addition, we observed that selective HLA-A down-regulation was significantly more frequent in MSI-H colorectal cancers. Menon et al (33) have previously reported an association of HLA-A negativity with a better prognosis in Notably, significant differences between MSI-H and MSS colorectal cancer were restricted to membraneous HLA-A staining, whereas general HLA-A staining differences did not reach statistical significance. These data may point to the functional Previous studies suggested the involvement of proteasome subunits and transporters of antigen presentation in immune evasion of colorectal cancer cells.…”

Section: Discussionmentioning

confidence: 87%

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

et al. 2005

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In colorectal cancer, the immune response is particularly pronounced against tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H tumors accumulate mutations affecting microsatellites located within protein encoding regions (coding microsatellites, cMS), which lead to translational shifts of the respective reading frames. Consequently, novel tumor-specific frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor cells, thus eliciting effective cytotoxic immune responses. To analyze whether the immunoselective pressure was reflected by the phenotype of MSI-H colorectal cancer cells, we compared here the expression of antigen processing machinery (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly developed APM component-specific monoclonal antibodies. In addition, we did a systematic analysis of mutations at cMS located within APM genes and b2-microglobulin (b 2 m). Total HLA class I antigen loss was observed in 12 (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at cMS of b 2 m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA class I antigen processing and presentation seem to be significantly more frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer the immunoselective pressure leads to the outgrowth of cells with defects of antigen presentation. (Cancer Res 2005; 65(14): 6418-24)

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Section: Discussionmentioning

confidence: 87%

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

et al. 2005

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“…The expression of HLA was categorized as normal when all tumor cells showed membranous expression, heterogeneous when tumor cells without expression coexisted with HLA-expressing tumor cells or absent when none of the tumor cells expressed HLA and the internal control (stroma, leukocytes, endothelium) was positive. 17 As previously described, an ocular grid, with a total surface area of 38 mm 2 , was used at a Â 200 magnification to count all leukocytes that were located intraepithelially in 25 different tumor fields of the tissue section. 10 Laminin was used to distinguish between intraepithelially, that is, leukocytes in the direct vicinity of tumor cells, and intrastromally located leukocytes (see Figure 1).…”

Section: Microscopic Evaluation Of Tumor Sectionsmentioning

confidence: 99%

Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

Menon

Rhijn

Morreau

et al. 2004

Laboratory Investigation

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The efficacy of tumor cell-immune cell interactions depends on a number of factors, for example, the expression of HLA-I on tumor cells, the type of immune cell, the accessibility of tumor cells for immune cells and the expression of immunogenic epitopes. We assessed infiltration of CD4 þ , CD8 þ , CD56 þ and CD57 þ cells in the tumor epithelium, tumor stroma and advancing tumor margin of 93 colorectal carcinomas and correlated this to clinicopathological parameters, the expression of HLA-A and HLA-B/C on tumor cells, the presence of a basal membrane (BM)-like structure surrounding tumor nodules and the presence of microsatellite instability/ mutator phenotype (absent MLH-1 expression). The median intraepithelial CD4 þ , CD8 þ , CD56 þ and CD57 þ cell infiltrations were 3, 23, 0 and 0 cells/mm 2 tumor, respectively. HLA-A/BC expression by tumor cells was normal in 28/43%, heterogeneous in 59/48% and absent in 13/9% of the cases. A BM-like structure surrounding the tumor nodules was absent, present and thick in 47, 38 and 15% of the cases. Six cases lost MLH1 expression. There was a positive correlation between leukocyte infiltration in the three compartments for CD4 þ , CD8 þ , CD56 þ (partly) and CD57 þ (all Po0.05) cell infiltration. Intraepithelial CD8 þ cell infiltration inversely correlated with HLA-A (P ¼ 0.04) and HLA-B/C expression (P ¼ 0.04). Intraepithelial CD57 þ cell infiltration inversely correlated with HLA-B/C expression (P ¼ 0.04). Moreover, intraepithelial infiltration of CD8 þ and CD57 þ cells was inversely correlated to the presence of a BM-like structure (P ¼ 0.003 and 0.04, respectively). Uni-and multivariate analyses showed that a lower tumor stage (P ¼ 0.004) and marked infiltration of CD8 þ (P ¼ 0.04) and CD57 þ cells (P ¼ 0.05) at the advancing tumor margin were independent prognostic factors for a longer diseasefree survival. Loss of MLH1 expression was correlated with a significantly higher intraepithelial CD8 þ and CD57 þ cell infiltration. We conclude that infiltration of CD8 þ and CD57 þ cells are important prognostic factors in colorectal cancer. However, their interaction with tumor cells is inversely correlated to the presence of HLA-I on tumor cells and a thick BM-like structure around tumor islets. Our data indicate that NK cells might play an important role in the immune surveillance in colorectal cancer patients.

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“…Expression of MHC class I alleles is frequently abnormal in colorectal cancer. 5 Previous immunohistochemical studies have indicated that loss of MHC class I expression in colorectal cancer is associated with poorly differentiated tumors and with those exhibiting mucinous differentiation. 5,6 No association has been found between overall MHC class I loss and either survival or metastatic spread.…”

mentioning

confidence: 99%

“…5 Previous immunohistochemical studies have indicated that loss of MHC class I expression in colorectal cancer is associated with poorly differentiated tumors and with those exhibiting mucinous differentiation. 5,6 No association has been found between overall MHC class I loss and either survival or metastatic spread. 7,8 Using high-throughput tissue microarray (TMA) technology, 9 we have analyzed MHC class I expression in a series of more than 450 paraffin-embedded colorectal tumor specimens.…”

mentioning

confidence: 99%

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis

Watson

Ramage

Madjd

et al. 2005

Intl Journal of Cancer

207

187

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Many colorectal tumors lose or downregulate cell surface expression of MHC class I molecules conferring resistance to T-cellmediated attack. It has been suggested that this phenomenon is due to in vivo immune-tumor interactions. However, evidence of the impact of MHC class I loss on outcomes from colorectal cancer is scarce. In our study of more than 450 colorectal cancers in tissue microarray format, we have shown that both high levels of MHC class I expression and absent MHC class I expression are associated with similar disease-specific survival times, possibly due to natural killer cell-mediated clearance of MHC class I-negative tumor cells. However, tumors with low level expression of MHC class I were found to confer a significantly poorer prognosis, retaining independent significance on multivariate analysis. The existence of these poor prognosis tumors, which may avoid both NK-and T-cell-mediated immune surveillance, has important implications for the design of immunotherapeutic strategies in colorectal cancer. ' 2005 Wiley-Liss, Inc.

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

Cited by 117 publications

References 44 publications

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis

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