Linking cancer exomes to cancer immunotherapy


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Ton Schumacher1
1Netherlands Cancer Institute, Amsterdam, The Netherlands

Abstract

There is now very strong evidence that human cancers can be recognised and destroyed by T lymphocytes.As a first example, antibodies against T cell checkpoint molecules such as CTLA-4 and PD-1 have shown clear effects in clinical trials in melanoma and also other human tumours. As a second example, infusion of autologous ex vivo expanded tumour-infiltrating T cells has resulted in tumour regressions in phase I/II trials in a number of centers including the Netherlands Cancer Institute.

An important gap in our understanding of these therapies is which epitopes are the targets in T cell-mediated tumour destruction. Such knowledge would be of value to steer T cell reactivity specifically towards these antigens.

With the aim to dissect therapy-induced T cell activity in human cancer, we have developed technologies for high-throughput analysis of T cell responses. Here I will discuss recent data that demonstrate how the combination of these technologies with cancer exome sequencing can be used to uncover T cell reactivity against mutated proteins. From the data obtained, we conclude that the T cell based immune system commonly interacts with the consequences of DNA damage in human melanoma. The ability to describe patient-specific T cell responses against mutated antigens forms an important first step towards the development of personalised cancer immunotherapy.