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  • Review Article
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Regulators of apoptosis: suitable targets for immune therapy of cancer

Nature Reviews Drug Discovery volume 4, pages 399–409 (2005)Cite this article

Key Points

  • The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of antitumour-reactive T cells and the use of 'therapeutic' vaccines. The latter aims at inducing cytotoxic T lymphocytes (CTLs) specific for tumour-associated antigens presented by cancer cells in the context of human leukocyte antigen (HLA) molecules.

  • Surprisingly, until recently only limited attention has been focused on identifying the most suitable targets for the induction of clinically relevant anticancer immune responses, the delineation of the most effective epitopes within these antigens and, finally, inclusion of sets of peptide epitopes best suited for targeting the disease in question.

  • The vast majority of malignancies are characterized by defects in apoptosis signalling, which is mediated by two group of apoptosis regulators: the BCL2 family (for example, BCL2, BCL-XL and MCL1) and the inhibitor of apoptosis proteins (IAP), such as survivin or melanoma IAP.

  • Such apoptosis regulators are therefore crucial cellular factors contributing to the pathogenesis and progression of cancer. Consequently, they represent very attractive targets for the design of new anticancer drugs, such as antisense oligonucleotides and small-molecule BCL2 inhibitors.

  • Notably, recently spontaneous cellular immune responses against these proteins have been identified as frequent features in cancer patients. Here, we summarize current knowledge of IAP and BCL2 family proteins as T-cell antigens, report the results of the first exploratory trials using these antigens for immunotherapy and discuss future opportunities, such as simultaneous targeting of several proteins or combination with conventional chemotherapy, because their expression in tumours is correlated with drug resistance and/or poor prognosis.

  • Immunotherapy based on survivin, BCL2 or MCL1 might also compromise endothelial-cell viability and interfere with tumour angiogenesis. Targeting survivin or BCL2 family members in angiogenic immunotherapy might therefore deliver two distinct and potentially synergistic treatment modalities using a common procedure.

  • In conclusion, a multi-epitope vaccine targeting regulators of apoptosis seems to be a promising, universal antitumour vaccine, which addresses both the tumour and the tumour stroma. Moreover, it synergistically boosts the effects of conventional cytotoxic therapies or radiation.

Abstract

Harnessing the immune system in the battle against cancer has been the focus of tremendous research efforts during the past two decades. Several means for achieving this goal, including adoptive transfer of tumour-reactive T cells, systemic or localized administration of immune modulating cytokines and the use of 'therapeutic' vaccines, have been explored. Anti-apoptotic molecules that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime candidates as vaccination antigens. Notably, spontaneous cellular immune responses against these proteins have frequently been identified in cancer patients. Here, we summarize current knowledge of IAP and BCL2 family proteins as T-cell antigens, report the results of the first explorative trial using these antigens in therapeutic vaccinations against cancer and discuss future opportunities.

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Figure 1: Principle of the interaction between tumour cells and CD8+ cytotoxic T cells and T-cell properties exploited for antigen-specific T-cell detection.
Figure 2: Apoptotic pathways.
Figure 3: Therapeutic strategies: co-targeting chemotherapy.
Figure 4: The role of survivin in angiogenesis.

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Acknowledgements

This work was funded in part by grants from the Danish Medical Research Council, The Danish Cancer Society and Danish Cancer Research Foundation.

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Authors and Affiliations

  1. Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, Dk-2100, Denmark

    Mads Hald Andersen, Jürgen C. Becker & Per thor Straten

  2. Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, Würzburg, D-97080, Germany

    Mads Hald Andersen & Jürgen C. Becker

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  1. Mads Hald Andersen
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  2. Jürgen C. Becker
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  3. Per thor Straten
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Correspondence to Mads Hald Andersen.

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Glossary

MAJOR HISTOCOMPATIBILITY COMPLEX

A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self.

ADJUVANT

An agent mixed with an antigen that enhances the immune response to that antigen upon immunization.

CpG DINUCLEOTIDES

Cytosine–guanosine pairs inDNA sequences. Oligodeoxynucleotide sequences that include CpG dinucleotides and certain flanking nucleotides have been found to induce innate immune responses.

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Andersen, M., Becker, J. & Straten, P. Regulators of apoptosis: suitable targets for immune therapy of cancer. Nat Rev Drug Discov 4, 399–409 (2005). https://doi.org/10.1038/nrd1717

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