Radiation and immunotherapy: a synergistic combination

Abstract

Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT.

Figures

Figure 1. Immunotherapy and the cancer immunoediting hypothesis.

In the immunoediting hypothesis, the tumor immune system balance shifts among tumor escape (to mutation-specific antigens), equilibrium, and elimination. Tumor escape (left) occurs in cases with poor antigenic expression, immunosuppressive cytokines, MDSCs, and expression of negative regulatory receptors on T cells (which engage cognate ligands on the tumor). In the equilibrium phase (middle), the tumor and the adaptive immune system coexist. Here, the immune system creates a growth-inhibitory environment and antigenic tumor outgrowths are kept in check. In tumor elimination (right), which often occurs in early tumor development, highly antigenic tumor clones are recognized and eliminated by both innate and adaptive immune systems. Various forms of immunotherapy (e.g., vaccines, adoptive cell transfer, targeted immunotherapeutics) aim to shift the balance from escape and equilibrium to elimination.

Figure 2. The role of RT in induction of the antitumor immune response.

At baseline, both the tumor immune microenvironment and the poor antigenicity of the tumor allow it to escape immune recognition. Targeted RT can induce increased antigenic expression, release pro-inflammatory cytokines (e.g., CXCL16) that recruit immune cells, promote antigen cross-presentation (HMGB-1 via TLR4), and induce tumor expression of death receptors. Anti-CTLA4–targeted immunotherapy can enhance the adaptive immune component by promoting antigen cross-presentation and T cell activation. Used together, RT and immunotherapy may have synergistic effects and may shift the tumor immune system balance toward elimination.