Proliferation of T-cell subsets that contact tumour cells in colorectal cancer

Abstract

It has been known for decades that solid malignancies in humans are associated with an infiltrate of inflammatory cells. A number of studies have found a clear positive correlation between the density of the lymphoid infiltrate and the prognosis of the patient [1][2][3][4]. This, together with the partial oligoclonality of carcinoma-infiltrating T cells [5], indicates that local immune responses to the tumours are likely to be occurring, although the precise nature of the response, and the reason for the survival of the tumours despite the anti-tumour response, are not known. It has been shown that in vitro, CD8 + T-IEL are able to spontaneously lyse colon carcinoma cell lines [6]. Around 20% of the stromal, but almost none of the intraepithelial CD8 + T cells express perforin in Dukes' A carcinomas, decreasing to just 3% in the stroma in Dukes' C cases [7]. Carcinoma-infiltrating Vd1 + T cells also lyse colon carcinoma cell lines [8], recognizing MICA and MICB on the tumour cells [9], and it has been shown in mice that Va14 + NK T cells lyse tumour cells [10]. As CD1, the target for human Va24 + NK T cells, is expressed on the intestinal epithelium [11], these cells may also respond to colorectal carcinoma cells.The phenotypes of the infiltrating lymphocytes have been investigated, and the proportions of CD4 + , CD8 + , TCRab + and TCRgd + cells reported vary considerably in different studies [12][13][14][15][16][17][18][19]. However, overall, it appears that CD8 + T cells localize to the epithelium, as in the normal gut. It has also been shown that the numbers of CD56 + and CD57 + NK T cells are increased within colorectal carcinomas compared with the normal gut [20,21].To increase understanding of the anti-tumour immune response, we have asked which subsets of tumour-infiltrating T cells are stimulated to proliferate in the T-IEL compartment, where T cells are in direct contact with the tumour, and in the stroma. We have also compared the proliferation frequencies observed for each T-cell subset with that observed in areas of maximal T cell stimulation in tonsils and Peyer's patches. In addition, T cells within intact cultured explants of colorectal carcinomas were studied to determine whether the T cell response is supported by factors in the tumour microenvironment. The explant model described here will also enable future studies of the functional relationship between the stromal and lymphoid elements of the tumour microenvironment. MATERIALS AND METHODS Tissues SUMMARYWe have investigated the proliferation rates of T-cell subsets in colorectal carcinomas using immunohistochemistry. It was found that the tumour-infiltrating T cells in contact with the tumour cells have a significantly higher frequency of proliferation than those in the stroma. In particular, the CD8 + intraepithelial lymphocytes (T-IEL) within the tumours have a significantly higher frequency of proliferation in comparison with CD8 + T cells in the stromal compartment or in any normal mucosal lymphoid tissues. It is possible that the proli...

Clinicopathologic Correlation of Up-regulated Genes Identified Using cDNA Microarray and Real-time Reverse Transcription-PCR in Human Colorectal Cancer

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Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

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Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk

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