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

The harnessing of one's own immune system to treat a cancer, termed tumour immunotherapy, is an extremely attractive proposition because of the potential for combining high selectivity with low toxicity. Tumour immunotherapy has progressed significantly in recent years with improved understanding of how to boost the normally weak immune response to tumours. Nevertheless, there is considerable need for more improvements to ensure this form of treatment is more widely and effectively applied. Successful immunotherapy depends on immune cells, such as killer T lymphocytes, becoming activated and homing to the tumour. However, tumour blood vessels limit access of T lymphocytes to the tumour. We have found that T lymphocytes are better equipped to control tumour growth when they express the homing molecule L-selectin. We predict this is because L-selectin expression factilitates access of killer T cells to the tumour where they can deliver their lethal hit. 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. The potential long-term benefit of this work is that it will direct novel strategies for improving the clinical application of tumour immunotherapy.

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.

The cell adhesion molecules that regulate leucocyte recruitment from the bloodstream to sites of infection, immunity and inflammation are targets for immunotherapy but the idea of promoting immune responses by manipulating immune cell homing is relatively unexplored. This research will benefit academics and biotechnology industries interested in how immune responses are regulated by immune cell trafficking and provide training for postgraduate and postdoctoral science and medical students. It also has educational benefit to undergraduate and school students in understanding the complex interplay between the immune system and cancer. There is currently a lot of interest in the use of immunotherapy to control cancers and this research will be of general interest to the public.
Identification of strategies to improve the effectiveness of immunotherapies will contribute to improving the nation's health by combating chronic debilitating diseases such as cancer, autoimmunity and chonic infection. Training of Ph.D. students and post-doctoral scientists in leucocyte trafficking expands the expertise base within the UK and internationally. Participation in public lectures, open days for schools, work experience placements for school and undergraduate students from within the UK and Europe disseminates ongoing research in Cardiff into immunotherapy.