Radiotherapy and Immunotherapy: Improving Cancer Treatment through Synergy

Radiotherapy is an important cornerstone in cancer treatment. Ionizing gamma-irradiation is capable of inducing DNA damage and consequential cell death in a precise and effective manner. In recent years it has become clear, however, that this is not the only relevant mechanism of action. Radiotherapy alters the immune composition of the tumor and influences upregulation of MHC I and cancer-testis antigens, inducing immunogenic cell death and supporting dendritic cell activation. Paradoxically, it also increases the relative ratio of regulatory T cells to CD4+ cells, which hampers an effective immune response. Nevertheless, the overall stimulating influence of irradiation on the immune system has been recognized and illustrated in preclinical studies as well as clinical case reports. There have been several attempts to use radiotherapy as an in situ vaccine. The basic rationale is a synergistic effect of different immune therapies like dendritic cell vaccination and CTLA-4 blockade with irradiation. Changes in the immune phenotype after radiotherapy can facilitate dendritic cell functioning. Immune therapy is also able to overcome the inhibitory pool of regulatory T cells through CTLA-4 inhibition, a weak point of radiotherapy. Although successful in preclinical models, there is still a lot of ground that needs to be covered. The optimal radiation dose is crucial, as well as timing and patient selection. Once these unknown parameters are explored, there is a lot of potential in the powerful combination of local immunization and systemic immune treatments for future novel cancer regimens.