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

Kloor, Matthias; Becker, Christina; Benner, Axel; Woerner, Stefan M.; Gebert, Johannes; Ferrone, Soldano; Doeberitz, Magnus von Knebel

doi:10.1158/0008-5472.can-05-0044

Cited by 148 publications

(136 citation statements)

References 32 publications

(30 reference statements)

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“…In addition, the frequency of APM deficiencies is increased in high-stage colorectal carcinomas and in those tumors with Kras mutations or microsatellite instability. 75 Gastrointestinal tumors may also express ligands for the stimulatory natural killer (NK) group 2, member D (NKG2D) receptor, which is expressed on NK cells and on some T cells. 76,77 NKG2D signaling results in perforin dependent cytolysis in NK cells and costimulation of cytotoxic T cells.…”

Section: Cd45r0mentioning

confidence: 99%

Dual Roles for Immunity in Gastrointestinal Cancers

Ferrone

Dranoff²

2010

JCO

205

158

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Histopathologic examination reveals that most human tumors are associated with diverse immune cell infiltrates, but the roles of host reactions in disease pathogenesis and prognosis remain to be fully clarified. Recent investigations in genetically engineered murine tumor models have uncovered dual functions for immune responses during cancer development and progression. Alterations in tumor cell gene expression profiles and coding sequences may trigger the activation of cytotoxic lymphocytes, which act to restrain tumor growth. In contrast, persistent inflammatory reactions, which may be driven by infection, environmental toxins, or impaired immune regulation, create a microenvironment that fosters tumor cell growth, survival, invasion, and dissemination. The dynamic interplay of these competing responses appears to be a critical event in cancer pathogenesis, with tumor promotion and immune evasion proving dominant in clinically evident disease. Nonetheless, longitudinal studies of patient cohorts have demonstrated that particular histopathologic and genetic signatures of cytotoxic lymphocyte reactions provide important prognostic information. Here, we discuss the dual roles of immunity in cancer development, focusing on gastrointestinal malignancies, given the depth of recent insights into the mechanisms underlying these tumors.

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Section: Cd45r0mentioning

confidence: 99%

Dual Roles for Immunity in Gastrointestinal Cancers

Ferrone

Dranoff²

2010

JCO

205

158

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“…For example, immune evasion mechanisms such as impairment or loss of the human leukocyte antigen class I-mediated antigen presentation (Bicknell et al, 1996;Cabrera et al, 2003;Kloor et al, 2005) or the expression of Fas ligand (Okada et al, 2000;Michael-Robinson et al, 2003) are frequent in MSI-H CRCs.…”

mentioning

confidence: 99%

High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability

et al. 2008

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High-level microsatellite instability (MSI-H) in colorectal cancer accounts for about 12% of colorectal cancers and is typically associated with a dense infiltration with cytotoxic CD8-positive lymphocytes. The role of regulatory T cells that may interfere with the host's antitumoural immune response in MSI-H colorectal cancers has not been analysed yet. Using an antibody directed against the regulatory T-cell marker transcription factor forkhead box P3 (FOXP3), regulatory T cells were examined in 70 colorectal cancers with known MSI status (MSI-H, n ¼ 37; microsatellite stable, n ¼ 33). In MSI-H colorectal cancers, we found a significantly higher intraepithelial infiltration with FOXP3-positive cells (median: 8.5 cells per 0.25 mm 2 vs 3.1 cells per 0.25 mm 2 in microsatellite stable, Po0.001), and a significantly elevated ratio of intraepithelial to stromal infiltration (0.05 vs 0.01 in microsatellite stable, Po0.001). CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's r ¼ 0.56 and 0.55, respectively). Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells. These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

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“…The coexistence of two different gene mutations, affecting both b2m alleles, has not been detected in melanoma but was recently shown to be of relevance for tumors of the microsatellite mutator phenotype, such as colorectal cancer in which an inactivation of DNA mismatch repair genes leads to an accumulation of gene mutation (34,35). Because melanoma is proposed to be a microsatellite mutator phenotype-negative tumor, we asked whether chromosome 15 instability contributes to h2m deficiency.…”

Section: Discussionmentioning

confidence: 99%

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

Paschen

Arens

Sucker

et al. 2006

Clinical Cancer Research

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Purpose:Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8 + Tcells, is known to be caused by mutations in the h2-microglobulin (b2m) gene. We asked whether abnormalities of chromosome 15, harboring the b2m gene on 15q21, in addition to b2m gene mutations, are causative for the HLA class I^negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the h2m-negative metastatic melanoma tissues of four different patients and analyzed them for b2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the b2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions.Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) b2m gene mutations.Melanoma cells can be effectively eradicated in vivo by the cytotoxic activity of HLA class I-restricted tumor antigenspecific CD8 + T cells as recently shown in clinical trials of adoptive T-cell transfer (1, 2). However, these studies also showed that adoptively transferred T cells infiltrating the metastasis not only act as cytotoxic immune effectors but also as immune editors (3, 4) selecting for tumor cell variants that escape immune surveillance by down-regulation of antigen expression (1). Besides antigen down-regulation, other properties of melanoma cells that interfere with T-cell effector function have been described, such as release of immunosuppressive cytokines (5, 6), release of Fas ligand-bearing microvesicles (7), and alterations in the surface presentation of HLA class I molecules (8-10).HLA class I molecules are heterodimeric noncovalently associated complexes consisting of the constant h2-microglobulin (h2m) light chain and the variable HLA heavy a chain. Irreversible alterations in the HLA class I phenotype of melanoma cells, such as loss of a single HLA allele, an HLA locus, or an HLA haplotype, are generally caused by

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

Cited by 148 publications

References 32 publications

Dual Roles for Immunity in Gastrointestinal Cancers

Dual Roles for Immunity in Gastrointestinal Cancers

High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

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