ReviewAntigens for cancer immunotherapy
Introduction
Metastasis-induced changes are the main cause of death in patients with solid cancers [1], [2]. Systemic therapies are obviously needed to overcome cancer that has or is likely to spread, but with a few exceptions metastatic malignancies develop resistance to standard chemotherapies, which are also responsible for considerable morbidity and even mortality. There is evidence from clinical trials that, with immunological manipulation, T cells have the specificity and power to control cancers, with minimal side effects. However, patient heterogeneity leads to inconsistent results in response to immunotherapy. In the absence of biomarkers that reliably predict the clinical outcome of patients, these inconsistencies must lead to skepticism in the clinical community about the value of pursuing immunotherapy for advanced metastatic disease. What are the major impediments to the successful implementation of specific cancer immunotherapy? Clinical trials aimed at active cancer immunotherapy need to make many decisions regarding dose, route, regime, adjuvant, and antigen. While each link in this chain is crucial to success, the very concept of specific cancer immunotherapy hinges on the choice of antigens. Indeed, a critical debate centers on whether ‘rejection antigens’ exist at all for spontaneous human cancers. Here we consider features of antigens that might influence the immune response to them, and examine evidence from the literature that particular kinds or combinations of antigens have therapeutic potential. Most of this review is implicitly concerned with active immunotherapy—‘vaccination’ to arouse anti-tumor T cell responses in the setting of advanced or minimal residual disease.
Section snippets
Antigen discovery
The initial molecular characterization of T cell determinants on tumors marks a cornerstone of immunology, and the ongoing discovery of new antigens is an important field of research. The first MHC class I-restricted human tumor antigens were defined using a genetic approach, using tumor-reactive T cells from a patient to distinguish targets transfected with tumor-derived cDNA or cDNA pools encoding the antigen(s) [3]. Although modified versions of this approach can be efficient [4], the
Heterogeneity within tumors
The hallmarks of cancer are genetic, epigenetic, and usually chromosomal changes that provide a growth advantage to malignant cells, by allowing them to evade the normal restraints on proliferation and migration [74], [75], [76]. In some cases, cancers derive from stem cells [77] which themselves possess some characteristics of malignancies, such as indefinite self-renewal and some of the requirements of metastasis. In this model of cancer evolution, a long-lived stem cell accumulates mutations
Multiple checkpoints to self reactivity
T cells are subject to recessive and dominant mechanisms of tolerance, both essential to avoid autoimmune sequelae, and both with important consequences for the development of anti-tumor immune reactions. Recessive tolerance – deletion or functional inactivation of T cells – operates at several levels. In the thymus, the ectopic expression of many, otherwise tissue-restricted, self antigens limits the high avidity naïve repertoire escaping to the periphery [109]. For example, human medullary
Antigens targeted by immunotherapies in clinical trials
The natural advantage of TSA as immunogens and as targets of an effective immune response is clear from the above data: mutations conferring selective advantages should be present on the tumor initiating cells, a relatively unblunted repertoire of cognate naïve T cells would be generated in the thymus, and the risk of autoimmunity from T cells targeting TSA would be eliminated. A parallel to the effective T cell responses mounted against pathogens is obvious. However, contrasted with the vast
Conclusions
Clear patterns emerge when the properties of known cancer determinants and their source antigens are considered in the light of our current understanding of antigen presentation and immune tolerance. There is an urgent need to identify and learn more about the targets of successful immune responses in a wider range of cancers, across statistically meaningful samples of patients. Of equal importance is establishing adequate models to test the safety of broadly targeted, defined vaccines. As the
Acknowledgements
We thank Prof Peter O’Rourke for statistical assistance. M.A.N. is a recipient of an Australian Postgraduate Award. J.A.L. was partially supported by a donation from Suncorp-Metway Ride-for-Research and the National Breast Cancer Foundation, Australia. C.W.S. acknowledges the support of Atlantic Philanthropies, the Queensland Cancer Fund, and the National Health and Medical Research Council of Australia.
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