PD-1 blockade enhances radio-immunotherapy efficacy in murine tumor models

Abstract

It has become increasingly clear in cancer treatment that radiotherapy can be enhanced by immunotherapy. In the present study, we evaluated a novel triple combination therapy consisting of local radiotherapy, intratumoral CpG, and systemic PD-1 blockade in lung cancer models. The efficacy of a novel triple therapy was examined by recording tumor volume and survival time. The immunologic effects of this novel triple therapy were evaluated by the frequency and percentage of immune cells and cytokines using flow cytometry. This triple combination proved more effective than its subcomponents and its positive antitumor effects included reducing tumor growth and improving host survival. The antitumor effect was not only observed in directly irradiated tumors but also in at distant tumor sites in a CD8+ T-cell-dependent fashion. Phenotypic analyses of CD8+ T cells revealed that the triple combination therapy increased the percentage of effector memory T cells in the spleen. Furthermore, the combination therapy significantly increased the frequency of IFN-γ and TNF-α-positive-CD8+ tumor-infiltrating lymphocytes (TIL) and mature-activated dendritic cells (DCs) within treated tumors, indicating that the antitumor effects likely depend on the activation of a DC subset specialized in antigen crosspriming to induce cytotoxic lymphocyte (CTLs). In addition, the triple therapy reduced immunosuppressive factors, like regulatory T cells (Tregs) in the spleen and tumor microenvironment while inducing the robust systemic antitumor effect. Finally, the triple treatment was, indeed, well tolerated and had a little effect on the hemogram and lung. These results suggest that this triple therapy promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation.