Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes

Aims: Colorectal cancers deficient in DNA mismatch repair (MMR) are often characterized by the presence of numerous intraepithelial lymphocytes (IELs). These CD8+ T cells selectively express CD103, which is upregulated locally by transforming growth factor (TGF)-beta, and adhere to E-cadherin expressed by mucosal epithelia. Many of these cancers also possess inactivating mutations in the type II TGF-beta receptor and are believed to be insensitive to TGF-beta. The present study aimed to explore whether such refractoriness to TGF-beta is an independently contributing factor to IEL retention. Methods and results: A panel of colorectal cancers enriched for DNA MMR deficiency was examined by immunohistochemistry to explore the expression levels and localization of various components in the TGF-beta signalling pathway. Logistic regression was then carried out in order to identify predictors of elevated lymphocytic infiltration independent of DNA MMR status. Increases in Smad4 expression, tumour cell proliferation and TGF-beta secretion each emerged as independent predictors of marked lymphocyte infiltration. Conclusions: These results strongly support the hypothesis that refractoriness to normal TGF-beta signalling in colorectal cancers plays a role in the retention of lymphocytes within tumour epithelium. Since IEL infiltration is an independent predictor of favourable prognosis, the TGF-beta pathway may represent an important therapeutic target.