Synergizing radiation therapy and immunotherapy for curing incurable cancers. Opportunities and challenges

Abstract

The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics. Evidence suggests that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (eg, radiation) later in the disease process. Indeed, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. As monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in crosspriming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research. This review examines mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses as well as preclinical systems demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy.

Figure 1

Antigen release from dying tumor cells can activate immune responses. Irradiation induces death of cancer cells. As these cells die, they are taken up by scavenger cells called antigen-presenting cells. These antigen-presenting cells then travel to regional lymph nodes where they present antigen to T cells, initiating or potentiating an antitumor immune response. Activated tumor-specific T cells can then traffic to areas of tumor to participate in immune-mediated tumor killing.

Figure 2

Irradiation modulates tumor-cell phenotype and increases immune recognition. Irradiation can cause (a) upregulation of chemokines and adhesion molecules, providing signals for T cells to come to areas of tumor, (b) upregulation of MHC molecules and tumor-associated antigens, making it easier for T cells to recognize tumor, and (c) upregulation of Fas and downregulation of regulatory T cells, making it easier for cytotoxic tumor-specific T cells to kill tumor.

Figure 3

Multiple mechanisms of synergy of radiation therapy and immunotherapy.