Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

Buckowitz, Annick; Knaebel, H. P.; Benner, Axel; Bläker, Hendrik; Gebert, Johannes; Kienle, Peter; Doeberitz, Magnus von Knebel; Kloor, Matthias

doi:10.1038/sj.bjc.6602534

Cited by 226 publications

(217 citation statements)

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“…Similarly, colorectal cancers with microsatellite instability are characterized by tumor-infiltrating lymphocytes and also carry a relatively favorable prognosis in spite of being higher grade. 30 Whether the presence of immune infiltration is itself the mechanism responsible for the improvement in prognosis or it simply represents an epiphenomenon of other molecular processes linked with better clinical outcomes remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss

et al. 2009

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Intraepithelial tumor-infiltrating T cells have been correlated with improved outcomes in ovarian carcinoma, however, it is not known whether there is an association with disease stage, histological subtype, or BRCA mutation/expression. Two case series of ovarian carcinomas were included in the study; a retrospective series of 500 patients, and 40 prospectively collected cases fully characterized for BRCA1 mutation status and expression. Intraepithelial immune cells were assessed as present or absent by immunohistochemical staining of tissue microarrays. In the retrospective case series, the presence of intraepithelial CD8 þ T-cells correlated with improved disease-specific survival (P ¼ 0.027), whereas intraepithelial CD3 þ T cells did not (P ¼ 0.49). For serous ovarian carcinomas, the presence of intraepithelial CD3 þ and CD8 þ T-cells correlated with improved disease-specific survival (P ¼ 0.0016 and Pr0.0001, respectively). The presence of intraepithelial CD8 þ T cells was not associated with improved survival in endometrioid or clear cell carcinomas. On multivariate analysis, disease stage and CD8 þ T cells were found to be independently predictive of improved disease-specific survival, whereas grade, age at surgery, and type of adjuvant treatment were not. In the prospective patient cohort, intraepithelial CD8 þ T-cells correlated with the presence of mutation or loss of expression of BRCA1 through promoter methylation (P ¼ 0.019). Intraepithelial CD8 þ tumor-infiltrating T-cells correlate with improved clinical outcomes for all stages of ovarian cancer; this association is restricted to the serous ovarian cancer subtype, and is an independent prognostic factor on multivariate analysis. The presence of intraepithelial CD8 þ T cells also significantly correlates with loss of BRCA1. rates to chemotherapy and the demonstrated improvements in median overall survival, fewer than 40% of patients with advanced disease survive to 5 years. 3 Many potential molecular prognostic factors in ovarian cancer have been investigated (eg HER2, TP53). 4 Most factors were identified in small studies and have not been reproduced or independently validated, precluding clinical utility. In addition, mutations of the BRCA1 and 2 tumor suppressor genes have been associated with improved clinical outcomes 5-7 but the biologic mechanisms underlying these findings are not well understood to date.The prognostic significance of the host immune response, as defined by the presence of tumor-infiltrating lymphocytes, has been studied in ovarian

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Section: Discussionmentioning

confidence: 99%

Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss

et al. 2009

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“…However, while TILs might be expected to explain the increased apoptotic rate and improved prognosis of MSI-H cancers, it is likely that MSI-H cancers are intrinsically more prone to apoptosis, independently of T cell attack [73]. In addition, Buckowitz et al [74] and Chiba et al [52] suggested a protective role of functionally active lymphocytes directed against MSI-H CRCs, which may prevent tumor cell dissemination and metastasis formation in distant organs. Furthermore, it has been postulated that the abundance of CD8 + TILs found in MSI-H CRC might be due to the failure of these tumor cells to upregulateFasL.…”

Section: Role In Prognosismentioning

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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“…The anti-tumoural immune response against CRCs is apparently closely linked to the molecular pathogenesis of these tumours, and MSI-H CRCs typically present with features of a pronounced local immune response, for example a high density of tumour-infiltrating lymphocytes with a high proportion of activated and cytotoxic CD8-positive lymphocytes (Dolcetti et al, 1999;Smyrk et al, 2001;Phillips et al, 2004;Jenkins et al, 2007). In line with the pronounced immunogenicity of MSI-H CRCs, these cancers rarely develop metastases in distant organs and have a comparably good prognosis (Buckowitz et al, 2005;Popat et al, 2005) in spite of a large tumour mass at the primary localisation (Wright et al, 2000).…”

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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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Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

Cited by 226 publications

References 40 publications

Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss

Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss

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

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

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