Tumour escape from the immune response

This Symposium in Writing revisits an area of central importance to immunotherapy previously examined almost 5 years ago in a collection of papers in this Journal titled “Tumour escape from the immune response: the last great hurdle for successful immunotherapy of cancer?” [1]. Unfortunately, it is true to say that most of these hurdles have still not been satisfactorily overcome, but it is clear from the present papers that a great deal of progress has been made in understanding the mechanisms involved in tumour escape and in identifying new ones which need to be neutralised. We begin with an overview of many of the major mechanisms of tumour escape, provided by Rees’ group (Ahmad et al.) introducing the concept of the ever-changing balance between immunoactivatory and immunosuppressive effects within the tumour environment, leading to coevolution of tumour and immune response in their murine models. This concept is discussed in greater detail in the clinical context by Anichini et al., who suggest a six-point plan for overcoming these obstacles to successful immunotherapy of human melanoma.

The mechanisms influencing this balance between antitumour and tumour-suppressor effects are manifold. They include several suppressive agents, not only the well-known TGF-β and other cytokines, but also recently recognised factors like indoleamine 2,3-dioxygenase (Ahmad et al.) which block T-cell function. The much-investigated area of the influence of tumours on altered T-cell signal transduction has become less controversial with the development of more sophisticated techniques and the accumulation of data confirming the widespread occurrence of such phenomena (Whiteside). The review by Malmberg focuses on one of the major contributors to TCR malfunction—oxidative stress—and how to counteract this. Another possible approach for evading the problem of altered signal transduction is presented by Baxevanis and Papamichail using genetically modified chimeric T-cell receptors (TCRs). Associated with a successful immune response but representing an important “resistance” mechanism is the well-known occurrence of decreased expression of MHC molecules and tumour antigens illustrated in murine models by Ahmad et al. and discussed in detail for human tumours by Garrido’s group (Algarra et al.). Application of chimeric TCRs would also render this common tumour escape mechanism less serious (Baxevanis and Papamichail). Decreased levels of expression of MHC molecules may increase sensitivity of tumours to MHC-unrestricted natural killing, but again, a complex balance of activatory and inhibitory receptors on NK cells (and T cells) and their ligands on tumour cells will determine the final outcome of the response, as presented by Solana’s group (Tarazona et al.). Finally, clonal exhaustion of chronically antigenically stressed T cells leading to immunosenescence is put forward as a factor contributing to tumour escape by Effros.

This collection of reviews, each covering both the general aspects of tumour escape from immunity and then focusing on a particular issue close to the author’s heart, illustrates not only how far we have come in the 5 years since the last Symposium in Writing on tumour escape, but also how far we have still to go before finding definitive solutions to any of these problems.