All in the head: obstacles for immune rejection of brain tumours

Tumour immunology and immunotherapy is a highly active field, a clinical testing ground for cutting edge immunological techniques and concepts. But this is after many years of fundamental advances in basic immunology. In this article we suggest that immunotherapy for brain tumours cannot be rationally advanced as rapidly as that for tumours in other sites. Our understanding of anti-tumour immune responses in the brain is sketchy and frequently extrapolated from other tissues having little in common with the central nervous system (CNS). The result is that current clinical trials are built upon shakier foundations, with the somewhat naive optimism that what is looking hopeful for other tumours will also be applicable to cerebral malignancies. But of course it is easy to criticise such well-meaning attempts to treat currently incurable cancers. In the basic and preclinical domain, brain tumour models that are readily applicable to the design of future immunotherapies are only in their infancy. The ideal transplantable tumour that reiterates the key features of a malignant primary astrocytoma (poorly immunogenic, infiltrative but non-metastatic, expressing multiple mechanisms mediating immune escape) has yet to be discovered. In the meantime, we must use individual model tumours and limit the scope of the conclusions that we make from each system. Moreover, we must overcome the significant technical difficulties encountered as we strive to preserve brain integrity, whilst implanting tumours in this unique site. Or we can look to genetic models, in which there is the development of `spontaneous' brain tumours (in some cases aided by the intracerebral delivery of a viral vector) incorporating many of the genetic features and heterogeneity typical of spontaneous human cancer. However, these models have generally been constructed to address genetic and pathological issues and they present a significant challenge for interpretable immunological studies.