Combining radiotherapy and immunotherapy: a revived partnership

Abstract

Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.

Figure 1. A model for the role of ionizing radiation in promoting cross-presentation of TAA and activation of anti-tumor T cells

It is well-established that dendritic cells (DC) can efficiently uptake tumor associated antigens (TAA) from apoptotic and necrotic tumor cells and present them to both CD4+ and CD8+ cytolytic T cells (CTL), a process termed cross-presentation. By killing tumor cells ionizing radiation can promote this process. In the presence of adequate “danger signals” that induce DC maturation and up-regulation of co-stimulatory molecules CD80 and CD86, tumor-specific T cells are activated to produce pro-inflammatory cytokines and become effectors capable of killing the tumor cells. Recognition and killing of tumor cells by CTL may be further enhanced by the radiation-induced up-regulation of Fas and/or MHC I molecules on the tumor cells.