DNA Repair Mechanisms as a New Target in Head and Neck Cancer

Abstract

Until recently, radiotherapy was viewed solely from a tumour cell-autonomous perspective, whereby successful therapy resulted from inflicting breaks in nuclear DNA above an unspecified threshold that exceeded the tumour cell’s capacity for repair. Greater understanding of the importance of non-tumour cell-autonomous, immunological aspects of radiation-induced cell death in the context of the tumour micro-environment (TME) has altered this rather narrow perception. We now know that clinical responses to radiotherapy are inextricably linked to the immune system: loco-regional radiotherapy can trigger abscopal, immune-mediated responses at distant unirradiated sites (albeit rarely), while patients who are pathologically or iatrogenically immunosuppressed may derive less benefit from radiotherapy. The intrinsic biology of individual tumours, their associated microenvironments, and the physical characteristics of the delivered radiation, can all influence the immunogenicity of radiotherapy. By understanding and modulating cross-talk between molecular responses to radiation-induced DNA damage, associated mechanisms of cell death and subsequent innate and adaptive immune responses, we may be able to improve clinical outcomes of radiotherapy. In this chapter, the focus will be on mechanisms of DNA damage repair and how tumours exploit alterations in these to enhance their survival. However, tumour cell-intrinsic aberrations in DNA repair can render tumour cells vulnerable to the effects of radiotherapy and this may be enhanced further by rational use of targeted DNA damage-response inhibitors. In particular, we will focus on how disordered DNA repair and its pharmacological modulation through ataxia telangiectasia and Rad3-related kinase inhibition can lead to radiation-induced immunostimulation and how this can be exploited further in the clinic through the use of specific immunotherapies, such as immune checkpoint blockers. As part of the discussion, specific mechanisms of radiation-induced cell death will be discussed, with emphasis on mechanisms of triggering immunologically visible, pro-inflammatory modes of cell death.