Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status

Michael-Robinson, Julie M.; Biemer-Huttmann, A.; Purdie, David M.; Walsh, Michael D.; Simms, Lisa A.; Biden, Kelli G.; Young, Joanne; Leggett, Barbara A.; Jass, Jeremy R.; Radford‐Smith, Graham

doi:10.1136/gut.48.3.360

Cited by 172 publications

(155 citation statements)

References 19 publications

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“…Stromal MSI presented in this study might be due to the methylation of mismatch repair enzymes in stromal cells, although the identification of the enzyme remains unclear. Previously, it was shown that high-level MSI (MSI-H) tumours are more likely to be right sided than their low-level MSI (MSI-L) or MSI stable counterparts (Michael-Robinson et al, 2001;Ward et al, 2001). In the present study, while MSI frequencies in both the epithelium and stroma were high in right-side (43, 50%) as compared to left-side lesions (29, 36%), the difference did not reach statistical significance.…”

Section: Discussioncontrasting

confidence: 90%

“…However, the contribution of stromal cells to the generation and progression of epithelial neoplasia has not been thoroughly investigated. Although genetic alterations are frequently observed in many benign and malignant epithelial tumours in the form of microsatellite instability (MSI) (Michael-Robinson et al, 2001;Ward et al, 2001), the possibility of genetic abnormalities in the background microenvironment of these tumours has generally not been addressed properly. However, recent findings indicate that loss of heterozygosity (LOH) may be frequent in mammary stromal tissue in breast cancer patients (Moinfar et al, 2000).…”

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confidence: 99%

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Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma

et al. 2003

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Differential microsatellite instability (MSI) in tumour epithelial and stromal compartments has not been well examined for colorectal cancers. Using laser-captured microdissection, separate specimens of these compartments of 40 sporadic colorectal cancers were sampled and MSI was tested with four markers. To examine the relation between the MSI phenotype in the stroma and other genetic events and histopathological features, p53 and K-ras gene mutations were analysed, and the expression of p53, hMLH1, and hMSH2 protein was determined by immunohistochemistry. Microsatellite instability positive results were obtained for both epithelium (34%) and stromal tissue (41%). While MSI in epithelium correlated with differentiation and Dukes' stage, that in stroma demonstrated an inverse relation, being particularly frequent in well-differentiated adenocarcinomas (54%) and Dukes' A lesions (55%). Further, a significant inverse correlation between p53 protein overexpression in the epithelium and MSI in the stroma was found (P ¼ 0.02475). The results suggest an alternative pathway of carcinogenesis involving stromal genetic instability in the development of colorectal cancers.

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Section: Discussioncontrasting

confidence: 90%

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confidence: 99%

Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma

et al. 2003

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“…Guidoboni et al [72] showed a significantly higher prevalence of activated CD8 + IEL in MSI+ versus MSI-CRC, suggesting that the occurrence of a local cytotoxic immune response may be the major determinant of the good clinical course of these MSI+ CRC patients. Dolcetti et al [71] and Michael-Robinson et al [73] demonstrated that the increased frequency of TILs associated with MSI-H cancers are only weakly or moderately correlated with tumor apoptosis. 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].…”

Section: Role In Prognosismentioning

confidence: 99%

“…Dolcetti et al [71] and Michael-Robinson et al [73] demonstrated that the increased frequency of TILs associated with MSI-H cancers are only weakly or moderately correlated with tumor apoptosis. 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.…”

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 number of intraepithelial CD3ϩ cells in the 5 most infiltrated fields were counted and the average number of the CD3ϩ cells/1,000 neoplastic cells was scored as low (Ͻ50), moderate (51-70) or high (Ͼ71). 20 …”

Section: Immunohistochemistrymentioning

confidence: 99%

Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

Kono

Takahashi

Amemiya

et al. 2001

Intl Journal of Cancer

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We have identified that HER-2/neu-derived peptides are naturally processed as tumor rejection antigens recognized by tumor-specific, HLA-A2-restricted cytotoxic T lymphocytes in gastric cancer. To evaluate candidates for immunotherapy using HER-2/neu-derived, HLA-A2-restricted peptides, we examined the frequency of HLA-A2 relating to HER-2/neu overexpression or the infiltrating grade of tumorinfiltrating lymphocytes (TILs) in Japanese patients with gastric cancer. HER-2/neu-overexpressing tumors detected by immunohistochemistry amounted to 19% of primary gastric cancers and HLA-A2-positive patients with gastric cancer were 31% of primary gastric-cancer cases. Finally, gastriccancer patients with both HLA-A2-positive and HER-2/neuoverexpressing tumors amounted to 6.6% of these cases. There was no significant difference in the infiltrating grade of TILs between gastric cancers overexpressing HER-2/neu and those that did not. Gastric cancer is 1 of the most common cancers occurring in Japan today. The control of gastric cancer at advanced stages still remains difficult, despite various treatments such as gastrectomy with extensive lymphadenectomy 1 and surgery combined with chemotherapy. 2 We and others reported that MHC class I-restricted cytotoxic-T lymphocytes (CTLs) from gastric-cancer patients can react specifically against autologous tumor cells. [3][4][5][6] Adoptive immunotherapy based on gastric cancer-specific CTLs, or vaccinations based on the MHC class I-associated tumor antigens that they recognize, represent alternative therapeutic approaches. The presence of tumor-associated antigens recognized by gastric-cancer-specific CTLs restricted by HLA-A31 6 or HLA-A2.1 molecules 4 has been demonstrated, although the nature of these antigens has not been defined. Moreover, we have identified that HER-2/neu-derived peptides are naturally processed as tumorassociated antigens recognized by tumor-specific, HLA-A2-restricted CTLs in gastric cancer. 7 Thus, HER-2/neu-derived peptides may be considered as candidates for tumor-specific immunotherapy such as tumor vaccination in patients with gastric cancer.The HER-2/neu protooncogene encodes a 185-kDa transmembrane glycoprotein with tyrosine-specific kinase activity. 8 The HER-2/neu protooncogene is amplified and overexpressed in approximately 30% of human ovarian and breast tumors 9 and in 20% of gastric cancers. 10 HLA-A2-restricted CTL epitopes derived from HER2/neu recognized by ovarian-11,12 and breast-13 cancerspecific CTLs have previously been defined, in addition to those specific for gastric cancer. The identification of several new HLA-A2-restricted CTL epitopes from HER-2/neu that can activate CTLs from healthy donors and patients with advanced ovarian carcinoma has also been reported. 14,15 These results indicate that HER-2/neu-derived peptides could be broad targets for immunotherapy against these types of cancers. It is important to evaluate candidates for tumor vaccination with HER-2/neu-derived peptides in patients with gastric cancer. Because it has...

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Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status

Cited by 172 publications

References 19 publications

Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma

Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma

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

Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

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