Combinations of immunotherapy and radiation in cancer therapy

Abstract

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.

Keywords: abscopal effect; clinical trials; immunotherapy; ionizing radiation; microenvironment; radiotherapy; tumor immunity.

Figure 1

Mechanisms of immune suppression in the tumor microenvironment. Tumors utilize multiple mechanisms for evading the immune system. Tumor cells can down-regulate expression of MHC-I, making them poor targets for CTL mediated killing. Along with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), they can express PD-L1 and PD-L2, which inhibit CTL function through the PD-1 receptor. Tumors make other soluble factors that also inhibit CTLs. Hypoxia in tumors induces HIF-1, driving the production of SDF-1, which acts as a chemokine to attract MDSCs and TAMs to the tumor microenvironment through the receptor CXCR4. These MDSCs and TAMs secrete cytokines such as IL-10 that promote a regulatory phenotype among intratumoral DCs, induce Tregs, and directly inhibit CTLs. Other myeloid-derived factors that inhibit CTL activity include TGF-β, reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), and arginase and nitric oxide synthase (NOS), which are enzymes that deplete l-arginine, an important metabolite for CTL function.

Figure 2

Ionizing radiation induces immunogenic cell death of tumors, which facilitates cross-priming of CTLs. Ionizing radiation induces translocation of calreticulin (CRT) to the tumor cell membrane, which acts as an “eat me” signal to dendritic cells (DCs), facilitating receptor mediated endocytosis through CD91. This makes tumor antigens available for cross-presentation on MHC-I for priming of tumor-specific T-cells. Radiotherapy also induces the release of danger associated molecular patterns (DAMPs), such as ATP and HMGB-1, which are endogenous immune adjuvants that stimulate DC activation, inducing DCs to provide co-stimulatory signals to naïve T-cells, facilitating cross-priming of CTLs. Together, these processes constitute immunogenic cell death of tumor cells.