Combining radiotherapy and cancer immunotherapy: a paradigm shift

Abstract

The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.

Figure 1.

The balance between proimmunogenic and immunosuppressive effects of radiotherapy and tumor rejection. Radiation promotes the priming and effector phases of the antitumor immune response. Key molecular signals that promote priming of antitumor T cells by dendritic cells loaded with tumor antigens include exposure of calreticulin (CRT) and release of ATP and high-mobility group protein B1 (HMGB1). These signals are released by the tumor cells undergoing a radiation-induced immunogenic cell death and, together with interleukin 1β (IL-1β) lead to activation of tumor-specific T cells. Key molecular signals that promote the effector phase include the upregulation of chemokines CXCL9, CXCL10, and CXCL16, which attract activated T cells to the tumor. Tumor infiltration by T cells that produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) is facilitated by upregulation of vascular cellular adhesion molecule 1 (VCAM-1) on tumor endothelium. Radiation-induced upregulation of major histocompatibility complex class 1 (MHC-1), NKG2D ligands (NKG2DL), intercellular adhesion molecule 1 (ICAM-1), death receptor Fas, and costimulatory molecule CD80 on surviving tumor cells improves their recognition and killing by T cells. On the other hand, radiation activates immunosuppressive transforming growth factor β (TGF-β) cytokine and promotes accumulation of regulatory T cells (Treg) and protumorigenic M2 macrophages (MØ2). Data suggest that positive effects of radiation often predominate over negative ones but are insufficient to shift the balance of the immunosuppressive tumor microenvironment to achieve tumor rejection in the absence of targeted immunotherapy.

Figure 2.

A case of an abscopal response in a patient with metastatic, poorly differentiated thymic carcinoma treated in a trial of granulocyte-macrophage colony-stimulating factor (GM-CSF) and radiation (51). Top panels, computed tomography cuts with dose overlays of radiotherapy to the mediastinum. At the base of the left lung, outside the radiation field, a biopsy-proven metastasis is visualized (red circle). Bottom panels, this lesion regressed after radiotherapy and GM-CSF. Although the patient eventually progressed elsewhere in the body, this area never recurred, and the patient is alive with stable disease 38 months later. F/U = follow-up.