The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications

Abstract

By inducing DNA damage, radiotherapy both reduces tumor burden and enhances anti-tumor immunity. Here, we will review the mechanisms by which radiation induces anti-tumor immune responses that can be augmented using immunotherapies to facilitate tumor regression. Radiotherapy increases inflammation in tumors by activating the NF-κB and the Type I interferon response pathways to induce expression of pro-inflammatory cytokines. This inflammation coupled with antigen release from irradiated cells facilitates dendritic cell maturation and cross-presentation of tumor antigens to prime tumor-specific T cell responses. Radiation also sensitizes tumors to these T cell responses by enhancing T cell infiltration into tumors and the recognition of both malignant cancer cells and non-malignant stroma that present cognate antigen. Yet, these anti-tumor immune responses may be blunted by several mechanisms including regulatory T cells and checkpoint molecules that promote T cell tolerance and exhaustion. Consequently, the combination of immunotherapy using vaccines and/or checkpoint inhibitors with radiation is demonstrating early clinical potential. Overall, this review will provide a global view for how radiation and the immune system converge to target cancers and the early attempts to exploit this synergy in clinical practice.

Keywords: Checkpoint blockade; Immunotherapy; Radiotherapy.

Figure 1. Radiation activates inflammatory cytokine pathways

(Upper panel) Radiation-induced DSBs activate the alternative pathway for NF-kB activation by inducing the nuclear translocation of ATM. (Lower panel) Irradiated cells release nucleic acids into the cytoplasm that are transferred via gap junctions or endocytosis to DCs and are recognized by cGAS that activates the STING pathway.

Figure 2. Radiation induces T cell priming

In non-irradiated tumors, immature DCs cross-present certain antigens to induce immune tolerance in the DLN. Radiation induces T cell priming by facilitating immunogenic cell death resulting in antigen release and inflammatory signals. DCs cross-present neo-antigens (blue) or increase the presentation of antigens already cross-presented (green). DCs mature under inflammatory signals and migrate to the DLN to induce anti-tumor immune responses.

Figure 3. Radiation facilitates effector T cell responses

(Upper panel) Tumors inhibit immune responses via checkpoint blockade, Tregs, immunosuppressive cytokines, tumor-associated macrophages, myeloid derived suppressor cells and a disorganized vasculature. (Lower panel) Radiation induces chemokine release and vascular normalization that increases T cell infiltration. In addition, irradiated cancer cells induce peptide-MHC and Fas expression increasing their susceptibility to T cell recognition and killing. Finally, radiation induces the stromal presentation of antigen facilitating their direct and indirect killing by T cells.

Figure 4. Checkpoint blockade synergizes with radiotherapy to facilitate tumor regression

Radiation induces cross-presentation of antigen by DCs in the DLN. Since some DCs express CTLA-4 that mitigates the expansion of cytotoxic T cells, ipilimumab blockade of CTLA-4 promotes T cell expansion. These effector T cells then return to the tumor where cancer cells and stromal cells expressing PD-L1 or PD-L2 induce T cell apoptosis. Blockade of PD-1 using nivolumab or pembrolizumab prevents T cell apoptosis to facilitate tumor cell killing.