Irradiation immunity interactions

Abstract

The immune system can influence cancer development by both impeding and/or facilitating tumour growth and spread. A better understanding of this complex relationship is fundamental to optimise current and future cancer therapeutic strategies. Although typically regarded as a localised and immunosuppressive anti-cancer treatment modality, radiation therapy has been associated with generating profound systemic effects beyond the intended target volume. These systemic effects are immune-driven suggesting radiation therapy can enhance anti-tumour immunosurveillance in some instances. In this review, we summarise how radiation therapy can positively and negatively affect local and systemic anti-tumour immune responses, how co-administration of immunotherapy with radiation therapy may help promote anti-tumour immunity, and how the use of immune biomarkers may help steer radiation therapy-immunotherapy personalisation to optimise clinical outcomes.

Keywords: cancer immunology; immune system; radiation immune modulation; radiation therapy; tumour microenvironment.

Fig. 1

Anti‐tumour immunity and its manipulation by RT. Tumour‐specific immune responses are driven by a series of events including APC tumour antigen uptake and APC maturation (1), and APC‐mediated T cell selection and activation at the draining lymph node (2) that results in T cell expansion and differentiation into Tef (3) that lead to anti‐tumour immune responses (3). RT affects anti‐tumour immunity at the TME in several ways (green arrows indicate steps that can have a positive effect, whereas red arrows indicate steps that can have a negative effect). RT can promote anti‐tumour immunity by inducing ICD of cancer cells resulting in the release of DAMPs that aid antigen uptake and APC maturation (1), enhancing their capacity to selectively generate Tef (2 & 3). RT also improves cancer cell recognition by NK cells (3). Conversely, RT can also suppress anti‐tumour immunity and promote cancer growth and spread by enhancing tissue repair and chronic inflammatory responses via ROS, RNS and MMP effects. This results in ECM breakdown and angiogenesis that can promote metastasis (4) and the accumulation of immunosuppressive cells such as MDSCs, M2 Mac and Tregs and expression of PD‐1 and PD‐L1 (5) that inhibit anti‐tumour immune responses (6). The complex interaction of the immune system, the TME and RT, is mediated by direct cell–cell communication and via soluble factors including cytokine and chemokines and can have several consequences on tumour immunity depending on the context in which they are present. To monitor this complexity, multiple immune biomarkers may help personalise RT‐IO combinations aimed to counteract factors that have a negative effect on anti‐tumour immunity and/or promote factors that have a positive effect on anti‐tumour immunity (lower left and right panels). APC, antigen‐presenting cells; CAR T, chimaeric antigen receptor T cell; CTLA‐4, cytotoxic T lymphocyte‐associated protein 4; ECM, extracellular matrix; GzmB, granzyme B; ICD, immunogenic cell death; ICI, immune checkpoint inhibitors; IFN‐γ, interferon‐γ; LN, lymph node; Mac, macrophage; MDSC, myeloid‐derived suppressor cell; MMP, matrix metalloprotease; NanoMed, nanomedicine; NK, natural killer cell; PD‐1, programmed cell death protein 1; PD‐L1, programmed cell death ligand 1; PFN, perforin; RA, retinoic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; TAM, tumour‐associated macrophage; Tef, T effector cells; TLR, toll‐like receptor; TNF‐α, tumour necrosis factor‐α; Treg, T regulatory cells. Created with BioRender.com. [Colour figure can be viewed at wileyonlinelibrary.com]