Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations

Abstract

Radiation therapy is an established and effective anti-cancer treatment modality. Extensive pre-clinical experimentation has demonstrated that the pro-inflammatory properties of irradiation may be synergistic with checkpoint immunotherapy. Radiation induces double-stranded DNA breaks (dsDNA). Sensing of the dsDNA activates the cGAS/STING pathway, producing Type 1 interferons essential to recruiting antigen-presenting cells (APCs). Radiation promotes cytotoxic CD8 T-cell recruitment by releasing tumour-associated antigens captured and cross-presented by surveying antigen-presenting cells. Radiation-induced vascular normalisation may further promote T-cell trafficking and drug delivery. Radiation is also immunosuppressive. Recruitment of regulatory T cells (Tregs) and innate cells such as myeloid-derived suppressive cells (m-MDSCs) all counteract the immunostimulatory properties of radiation. Many innate immune cell types operate at the interface of the adaptive immune response. Innate immune cells, such as m-MDSCs, can exert their immunosuppressive effects by expressing immune checkpoints such as PD-L1, further highlighting the potential of combined radiation and checkpoint immunotherapy. Several early-phase clinical studies investigating the combination of radiation and immunotherapy have been disappointing. A greater appreciation of radiotherapy's impact on the innate immune system is essential to optimise radioimmunotherapy combinations. This review will summarise the impact of radiotherapy on crucial cells of the innate immune system and vital immunosuppressive cytokines.

Keywords: Immune system; Immunotherapy; Innate; Radiation; Radiotherapy.

Fig. 1

Immunostimulatory effects of irradiation in promoting a CD8+ anti-tumoural T cell response. Localised radiotherapy promotes the release of tumour-associated antigens (TAAs) that are captured and presented by surveying dendritic cells. The dendritic cells drain to regional lymph nodes, priming CD8⁺ T cells and CD4⁺ T cells. CD8⁺ T cells trafficking to the tumour is promoted by the chemokines CXCL9, CXCL10, and CXCL12.

Fig. 2

NK cell activation in response to tumour stimulation. NK cell activation signaling occurs through MIC-A/B binding to NKG2D. Activation signaling also occurs through NK surface receptors FC$\gamma R$III, and Natural cytotoxicity receptors (NCRs) NKp30, NKp46 and NKp44. HLA-B/C binding to members of the KIR family of receptors can be inhibitory. Upon activation, NK cells release granzyme/perforin to lyse tumour cells. The cytokines TNF and IFN mediate the immune response. Image adapted from Rosental et al. .

Fig. 3

Local Immunosuppressive effects of MDSCs. Tumour hypoxia promotes lactate uptake by MDSCs, upregulating HIF-1$\alpha$. iNOS promotes the expression of PDL1, downregulating NK and effector T cell function. TGF-$\beta$ production downregulates NK activation and promotes Treg expansion. IL-10 further contributes to Treg expansion and M2 polarisation of TAMs along with IL-6. Figure adapted from Jimenez and Yang .

Fig. 4

Immunomodulatory effects of radiation induced STING signaling. Radiation induces dsDNA breaks, activating cGAS and upregulating STING signaling, and promoting Type 1 interferon production. Additionally, radiation upregulates PD-L1 expressing MDSCs. MDSCs inhibit CD8⁺ T-cell effector functions and produce TNFα that promotes Treg production of TGF. CCL2 production downstream of STING signaling promotes MDSC and Treg recruitment. Treg production of TGF-$\beta$ further contributes to the immunosuppressive TME. Image adapted from McLaughlin et al. .