Abstract

T cell infiltrates are common in carcinomas, and correlate with a good prognosis. Hence, there is considerable therapeutic interest in promoting the activity of these cells and in reducing the local immunosuppressive environment of the tumour. In this regard, we investigate the regulation of tumour infiltrating lymphocytes (TILs) from the perspective of intraepithelial T lymphocytes (IEL), a very large but poorly understood T cell compartment, ordinarily resident in healthy tissues. In particular we have sought to understand how novel, locally expressed members of the 'B-7 supergene family' regulate the activities of IEL. Such genes, expressed in a tissue-specific fashion may likewise regulate TILs in specific tumour-types, and may make better targets for clinical intervention than the checkpoints that also regulate systemic T cells. We have characterised one such local B-7-like regulator expressed exclusively in the thymus and suprabasal keratinocytes that regulates mouse epidermal T cells, conferring on them a unique, rapid response mode to the types of tissue dysregulatlon that characterise the early stages of cell transformation. This is consistent with the increased susceptibility to cutaneous carcinomas of mice lacking intraepidermal T cells. We have now identified T cells in human skin with a very similar response mode, and propose that their regulation and enhancement is an appropriate clinical target for immunotherapy. Moreover, we have recently identified another B-7 related gene that is expressed specifically in the small intestinal epithelium, and which is critical to the regulation of intestinal IEL. We shall present these findings, and consider their possible relationship to biological and clinical aspects of tissue immunosurveillance.