T cells and the immunogenicity of immunotherapy
1King’s College London & The francis Crick Institute, London, UK
Some extraordinary clinical successes of immunotherapy have had game-changing effects on the way we view cancer biology and the interaction of the immune system with our tissues. In particular, the tissues where solid tumours form are commonly replete with resident T cells. gd T cells are prominent tissue-resident T cells in all vertebrates examined. We have shown that they make rapid innate-like responses to molecular markers of tissue perturbation, killing dysregulated cells, producing selective cytokines, and presenting antigen to CD8 T cells. Thus, these T cells can facilitate the immunogenicity of growing tumours. In seeking a better understanding of how tissue-resident gd T cells are regulated in situ in health and disease, we have identified organ-specific B7-like molecules that constitute de facto local checkpoints.
Although most studies of tissue-resident T cells have, for obvious reasons been conducted on mice, we have undertaken a characterisation of human tissue-resident T cells from healthy and tumour tissue in over 100 donors. Those studies emphasise the relatedness of Tumour Infiltrating Lymphocytes (TILs) with local T cells. With this knowledge, we are developing a programme of human gd T cell immunotherapy that may be particularly suited to adenocarcinomas of low mutation load or with high rates of tumour evolution.