Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

Abstract

Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50-60% of patients. It is part of therapy for around 40% of cancer patients who are cured of their disease. Until recently, the focus of this anti-tumour efficacy has been on the direct tumour cytotoxicity and RT-induced DNA damage. Recently, the immunomodulatory effects of RT on the tumour microenvironment have increasingly been recognized. There is now intense interest in potentially using RT to induce an anti-tumour immune response, which has led to rethinking into how the efficacy of RT could be further enhanced. Following the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology (IO) agents has emerged and established immunotherapy as a routine part of cancer treatment. Despite ICI improving outcomes in many cancer types, overall durable responses occur in only a minority of patients. The immunostimulatory effects of RT make combinations with ICI attractive to potentially amplify anti-tumour immunity resulting in increased tumour responses and improved outcomes. In contrast, tumours with profoundly immunosuppressive tumour microenvironments, dominated by myeloid-derived cell populations, remain a greater clinical challenge and RT may potentially further enhance the immunosuppression. To harness the full potential of RT and IO agent combinations, further insights are required to enhance our understanding of the role these immunosuppressive myeloid populations play, how RT influences these populations and how they may be therapeutically manipulated in combination with RT to improve outcomes further. These are exciting times with increasing numbers of IO targets being discovered and IO agents undergoing clinical evaluation. Multidisciplinary research collaborations will be required to establish the optimal parameters for delivering RT (target volume, dose and fractionation) in combination with IO agents, including scheduling to achieve maximal therapeutic efficacy.

Keywords: Immune checkpoints; Immuno-oncology agents; Immunotherapy; Radiation therapy; Radiotherapy.

Fig. 1

The choice of therapeutic agent in combination with radiotherapy may depend on the TME. Radiotherapy can drive the expansion and activation of T-cells in tumours with a T-cell rich TME. This leads to upregulation of PD-L1 and these tumours respond to ICIs. Conversely, tumours with a myeloid rich TME do not respond to ICI, RT drives further expansion and suppressive myeloid cells and may need to be combined with IO agents which re-programme myeloid cells and/or enhance T-cell priming and infiltration. ICI immune checkpoint inhibitor, IO immuno-oncology, M2 M2-polarised macrophage, mAb monoclonal antibody, MDSC myeloid-derived suppressor cell, RT radiotherapy, TME tumour microenvironment

Fig. 2

Radiotherapy induces a local anti-tumour immune response (a). Radiotherapy delivered to multiple sites may augment systemic responses (b). RT-induced immunogenic cell death stimulates the release of DAMPs and type 1 IFNs, which enhance antigen uptake and presentation by DCs. DCs present tumour antigens to T cell receptors, priming naïve T-cells to an effector phenotype. These T-cells migrate into the local tumour to exert their cytotoxic effects, or re-enter the circulation and migrate to distal, non-irradiated tumour sites (Panel A). At distal tumour sites, DCs may also activate T-cells against novel tumour antigens. RT delivered to multiple sites may therefore increase the quantity and diversity of migrating T-cells, enhancing the potential for systemic immune responses at non-irradiated sites (b). DAMPs damage-associated molecular patterns, DC dendritic cell, IFN interferon, MHC I major histocompatibility complex class I, RT radiotherapy, TCR T-cell receptor