Review
T-cell immune responses in the brain and their relevance for cerebral malignancies

https://doi.org/10.1016/S0165-0173(03)00141-3Get rights and content

Abstract

In order that cellular immune responses afford protection without risk to sensitive normal tissue, they must be adapted to individual tissues of the body. Nowhere is this more critical than for the brain, where various passive and active mechanisms maintain a state of immune privilege that can limit high magnitude immune responses. Nevertheless, it is now clear that immune responses are induced to antigens in the brain, including those expressed by cerebral malignancies. We discuss hypotheses of how this can occur, although details such as which antigen presenting cells are involved remain to be clarified. Antitumor responses induced spontaneously are insufficient to eradicate malignant astrocytomas; many studies suggest that this can be explained by a combination of low level immune response induction and tumor mediated immunosuppression. A clinical objective currently pursued is to use immunotherapy to ameliorate antitumour immunity. This will necessitate a high level immune response to ensure sufficient effector cells reach the tumor bed, focused cytotoxicity to eradicate malignant cells with little collateral damage to critical normal cells, and minimal inflammation. To achieve these aims, priority should be given to identifying more target antigens in astrocytoma and defining those cells present in the brain parenchyma that are essential to maintain antitumour effector function without exacerbating inflammation. If we are armed with better understanding of immune interactions with brain tumor cells, we can realistically envisage that immunotherapy will one day offer hope to patients with currently untreatable neoplastic diseases of the CNS.

Section snippets

Immune recognition of antigens

The role of the immune system is to maintain the functional integrity of the host in the face of biological threats arriving from the exterior (pathogenic microbes), or from within (neoplastic changes). It is clear that the necessity for such a defense system is organism-wide, at least for non-expendable, non-self renewing tissues and organs such as the brain. The only caveat that may be raised is if there is an efficient non-immunological defense mechanism. For the CNS, the physical protection

Effector stages of T-cell immune responses

Whilst the mechanisms responsible for the induction of spontaneous T-cell immune responses in the CNS are hypothetical, there are more direct data concerning the effector phase of the response. T cells infiltrating the brain parenchyma can be directly visualized in both clinical and experimental situations and in some cases, sufficient cells can be isolated for ex vivo functional tests.

T-cell immune responses to brain tumors in clinical and experimental situations

The principles of the induction of immune responses have been considered as well as how the effector phase of CNS responses may occur. The final outcome depends on the immune response that was induced and the efficiency of the effector phase of the response. In the case of tumors located in the CNS that will be considered in this section, simply observing whether a tumor is eliminated by an antitumor immune response is not always very enlightening. In order to understand whether and how immune

Concluding remarks

There is now compelling evidence that CD8+ T-cell immune responses occur in the CNS and that at least in experimental models, CD8+ T cells can mediate protective roles such as the elimination of tumor cells. However, spontaneous antitumor immune responses in humans are inefficient, yet the need for new therapeutic approaches in brain tumors such as malignant astrocytoma is particularly urgent. We thus need to understand how antitumor responses can be safely amplified, taking into account the

Acknowledgements

The work in our laboratory is partly supported by grants from OncoSuisse, the Association for International Cancer Research, the Fondation Lionel Perrier and the Ligue Genevoise Contre le Cancer.

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