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Dissecting the impact of L-selectin on T lymphocyte dependent tumour immunity

Ann Ager

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Medical Research Council (MRC)
T lymphocyte infiltration of tumours correlates with improved outcome in patients. However, tumours actively suppress T cell recruitment by inhibiting the expression of homing associated cell adhesion molecules and chemokines on blood vessels in draining lymph nodes and within the tumour. The overall effect is to limit priming of T cells to tumour derived antigens in lymph nodes draining the tumour. Even if T cells are primed, recruitment into the tumour will be restricted because tumour blood vessels fail to support T lymphocyte homing. Strategies that boost the localisation of effector T cells capable of tumour destruction within the tumour may improve the efficacy of immunotherapies to control tumour growth. Several studies link the expression of the leucocyte specific homing molecule L-selectin/CD62L and tumour growth but the underlying mechanisms are unknown. Since L-selectin is an essential lymph node homing molecule, the role of L-selectin in regulating tumour immunity may be to facilitate T cell priming and differentiation in response to tumour derived antigens in draining lymph nodes. However, studies using L-selectin knockout mice have shown that reduced control of tumour growth in these mice is not simply due to lack of cytotoxic T lymphocyte (CTL) generation but correlated with a markedly reduced recruitment of leucocyes into the tumour. This highlights an important role for L-selectin in regulating leucocyte recruitment into tumours. We have found that the rapid growth of primary tumours in L-selectin deficient mice is reduced by maintaining expression of L-selectin on T lymphocytes. These data demonstrate that T cell expressed L-selectin controls tumour immunity and reveal a novel way of promoting tumour immunity by altering expression of homing molecules on T cells. The aim of this proposal is to study the properties of these L-selectin enhanced T lymphocytes and to determine whether they could be used to treat tumours.

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