Several suggestions have been made that promoter methyla- tion of specific genes may indicate a particular tumour’s sensitivity to a drug. Such studies have yet to make an impact in the treatment of HNSCC. In the treatment of gliomas, it has been found that MGMT promoter methylation is a useful predictor of the responsiveness to alkylating agents such as Temozolomide [104]. Perhaps of more relevance is
that CHFR methylation predisposes cancer to increased sensitivity to taxanes [105] which may be a useful line of investigation as TPF-induction chemotherapy gains ground in HNSCC. Epigenetic alterations are particularly interesting as characteristics of cancer as they can potentially be reversed in drug treatment. A great number of epigenetically directed drugs are now entering clinical trials, particularly in the field of haematological malignancy. Demethylation agents such as 5-azacytidine and decitabine are now licenced for the treat- ment of myelodysplasia. The use of histone deacetylase inhibitors as single agents has limited usefulness but shows promise in combination with demethylating agents. The emergence of drug-resistant clones accompanying loss of DNA mismatch repair with MLH1 hypermethylation has been identified as a frequent issue in treatment failure in ovarian cancer. At least in vitro, this has been addressed by combination therapy with both demethylating agents and standard chemotherapy [106]. Clearly this field is in its infancy, and provided epigenetic therapy can be administered with acceptable toxicity; methylation assays are readily avail- able to demonstrate adequate pharmacodynamic effects.
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J. Bernier (ed.), Head and Neck Cancer: Multimodality Management, 107
DOI 10.1007/978-1-4419-9464-6_6, © Springer Science+Business Media, LLC 2011
Abstract The immune system plays a key role in the progression of head and neck cancer. A greater understand- ing of the important contribution of the dysregulation and evasion of the immune system in the development and evolution of head and neck cancers should lead to improved therapies and outcomes for patients. Head and neck cancer evades the host immune system through manipulation of its own immunogenicity, production of immunosuppres- sive molecules, and promotion of immunomodulatory cell types. Also, the immune system can be exploited to promote metastasis, angiogenesis, and growth. In this chapter, we review basic immunology as it relates to head and neck can- cer and discuss the theory of cancer immunosurveillance and immune escape. Current research on cytokines as biomark- ers, cancer stem cell tumor antigens, and immunotherapeutic strategies are presented.
Keywords Immunology • Immunotherapy • Head and neck cancer • Biomarkers • Immune evasion • Immune surveil- lance • Monoclonal antibodies
Introduction
The immune system plays a key role in the progression of head and neck cancer. A greater understanding of the impor- tant contribution of the dysregulation and evasion of the immune system in the development and evolution of head and neck cancers should lead to improved therapies and out- comes for patients. In this chapter, we review basic immu- nology as it relates to head and neck cancer and discuss the theory of cancer immunosurveillance and immune escape.
There has been a recent renaissance in the idea that nascent cancer cells are destroyed by the immune system before tumor formation can occur (termed immune surveillance).
Derangements in the immune system or alterations in the transformed cells may allow immune escape that allows the cancer to become manifest. Once tumor is established, there are a myriad ways in which it interacts with the immune system. Transcription factors such as NFk(kappa)B (nuclear factor kappa-light-chain-enhancer of activated B cells) and STAT3 (signal transducers and activators of transcription), which are usually dysregulated in tumor-promoting inflam- matory states in response to cytokine stimuli, are aberrantly activated in tumor cells and are intensively studied as possible targets for therapeutic intervention. Tumors themselves pro- duce cytokines such as TGF-b(beta), IL-6, and IL-10, which suppress cell-mediated antitumor immunity. In response to inflammatory stimuli, head and neck cancer cells also can express receptors which are involved in lymphocyte and den- dritic cell migration. Expression of these receptors by tumor cells, such as CCR7 and CXCR4, constitute immune exploi- tation of established signals intended for immune cells and have been associated with tumor invasion, metastasis, and cell survival, leading to treatment resistance. Another recently espoused theory is the idea that tumors are comprised of a heterogenous cell population in the tumor microenvironment that includes a special subpopulation of cancer stem cells (CSC) that are able to recreate the entire tumor phenotype and potentially evade immune recognition. These cells appear to be more resistant to conventional chemotherapy and radia- tion, and may not possess the same tumor antigen expression or T-cell recognition as non-CSC.
In head and neck cancer patients, there appear to be global alterations in the functional state of the immune system, as evidenced by changes in serum cytokines, chemokines and other immune-related biomarkers in cancer patients. There is considerable investigation focusing on the identification of serum biomarkers to monitor cancer progression, prognosis, treatment response, and relapse. Finally, we describe various immunotherapeutic strategies designed to utilize the immune system to stimulate elimination of cancer. These include cancer vaccines using tumor peptide antigens or viral, bacte- rial, and DNA-based vectors as well as tumor antigen-spe- cific monoclonal antibodies (mAb). The recent clinical efficacy of these FDA-approved mAb, including cetuximab
R.L. Ferris (*)
University of Pittsburgh Cancer Institute,
200 Lothrop Street, Suite 500, Pittsburgh, PA 15213 e-mail: [email protected]