Radiotherapy in Combination With Cytokine Treatment

Abstract

Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-α, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-α used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.

Keywords: cytokine; immunocytokine; immunogenic cell death; immunotherapy; radiotherapy.

Figure 1

Schematic representation of immunoadjuvant effects of cytokines in combination with radiotherapy treatment of tumors. Radiotherapy was shown to stimulate anti-tumor immunity by increasing expression of MHC class I molecules, NKG2D ligands or FAS/CD95 in tumor cells. RT induces production of chemokines such as CXCL9, 10, and 16 in tumor cells which attract effector T cells to tumor site. RT induces immunogenic cell death and exposure and release of danger-associated molecular patterns (DAMPs) such as calreticulin, HMGB1, ATP, or heat-shock proteins (HSPs). Moreover, RT-generated dsDNA activates via cGAS/STING pathway the IFN-β production in tumor cells as well as in dendritic cells (DC). All of these molecules facilitate the phagocytosis of dead tumor cells and uptake of released tumor antigens by DC. They activate immature dendritic cells (iDC) to process antigens, enhance the expression of MHC class I and II molecules and co-stimulatory molecules such as CD80, CD86, CD83 on its surface to become mature dendritic cells (mDC). In lymph nodes, mDC prime T cells to become effector cells which then exert direct cytotoxic effects on tumor cells or generate the proinflammatory milieu in tumors. TNF-α and IFN-α can directly exert apoptotic effects on tumor cells. GM-CSF mainly activates dendritic cells. IL-2, IL-2 immunocytokines (IL-2-ICKs), IFN-α, and IL-15 activate directly T cells and NK cells to become cytotoxic effector cells. Moreover, IL-15 can bind to its high affinity receptor IL-15Rα on DC and as a part of immunological synapse can enhance T cell functions.