Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors

Abstract

Radiotherapy (RT) utilizes the DNA-damaging properties of ionizing radiation to control tumor growth and ultimately kill tumor cells. By modifying the tumor cell phenotype and the tumor microenvironment, it may also modulate the immune system. However, out-of-field reactions of RT mostly assume further immune activation. Here, the sequence of the applications of RT and immunotherapy is crucial, just as the dose and fractionation may be. Lower single doses may impact on tumor vascularization and immune cell infiltration in particular, while higher doses may impact on intratumoral induction and production of type I interferons. The induction of immunogenic cancer cell death seems in turn to be a common mechanism for most RT schemes. Dendritic cells (DCs) are activated by the released danger signals and by taking up tumor peptides derived from irradiated cells. DCs subsequently activate T cells, a process that has to be tightly controlled to ensure tolerance. Inhibitory pathways known as immune checkpoints exist for this purpose and are exploited by tumors to inhibit immune responses. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T cells are two major checkpoints. The biological concepts behind the findings that RT in combination with anti-CTLA-4 and/or anti-PD-L1 blockade stimulates CD8+ T cell-mediated anti-tumor immunity are reviewed in detail. On this basis, we suggest clinically significant combinations and sequences of RT and immune checkpoint inhibition. We conclude that RT and immune therapies complement one another.

Keywords: CITIM 2015; Immune checkpoint inhibitors; Immunogenic cancer cell death; Immunotherapy; Out-of-field effect; Radiotherapy.

Fig. 1

Contribution of local and systemic effects of radiotherapy to tumor cell killing. Radiotherapy-induced increased generation of reactive oxygen species (ROS) induces DNA damage that is immediately sensed and, if possible, repaired (DNA damage response). Cells are arrested in the cell cycle and no longer proliferate. Senescent cells may result or the cells are driven toward death during the course of mitosis (mitotic catastrophe). Unrepaired DNA damage finally results in cell death. Additionally, systemic responses can be initiated arising from ROS and endoplasmic reticulum (ER) stress by modification of the tumor cell surface after exposure to ionizing radiation and by release of danger signals, inflammatory cytokines, exosomes and (modified) tumor antigens. Dendritic cells (DCs) mature are activated and initiate innate and adaptive immune responses. Ags antigens, CRT calreticulin, iDC immature DC, mDC mature DC

Fig. 2

Immune-modulating irradiation as a basis for combination of radiotherapy with checkpoint inhibitors. Immune-stimulating irradiation results in the release of damage-associated molecular patterns (DAMPs) and (modified) tumor antigens. Dendritic cells (DCs) are recruited and activated and take up the antigens (Ags). DCs then migrate to lymph nodes and cross-present the tumor Ags to T cells. The priming of T cells is highly controlled to avoid autoimmune reactions and to maintain self-tolerance. There are various ligand–receptor interactions between antigen-presenting cells such as DCs and T cells that regulate the T cell response to Ag. The up-regulation of the co-stimulatory molecules CD80 and CD86 on DCs in response to radiation-induced DAMPs delivers co-stimulatory signals to T cells. However, mostly pairs of co-stimulatory–inhibitory receptors bind the same ligand(s) (e.g., CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) both bind to CD80/CD86). Of note is that the inhibitory receptor is commonly up-regulated later on, namely after T cell activation. A longer-lasting T cell activation can therefore be achieved when antibodies designed to relieve immunosuppression such as anti-CTLA-4 are administered in addition to RT. Besides these immune-activating effects of RT, potentially deleterious effects exist. Tumor cells can up-regulate programmed cell death protein 1 ligand (PD-L1) in response to radiation. PD-L1 interaction with PD-1 on T cells then shuts down the cytotoxic T cell response within the tumor. This is another reason for combining RT with Abs that inhibit immune checkpoint proteins or the interaction with their respective receptors. Since anti-CTLA-4 and anti-PD-L1 use non-redundant immune mechanisms to enhance anti-tumor immunity and act at different time points during establishment of anti-tumor immune reactions, dual immune checkpoint inhibition in combination with RT might be the therapy of choice for the future