PD-1 Blockade Boosts Radiofrequency Ablation-elicited Adaptive Immune Responses Against Tumor

RFA(Radiofrequency ablation) is a widely used minimally invasive treatment for primary and metastatic cancer such as, hepatic cancer, colorectal cancer liver metastases, non-small cell lung cancer. Accumulating evidence show that RFA induced systemic tumor antigen-specific T cell responses. Our preliminary study also showed that dentrictic cells can be loaded and activated with lysate induced by RFA. However, RFA is not sufficient to prevent tumor recurrence in clinic, suggesting that duration and function of RFA-induced tumor-specific T cells are inadequate and the underlying mechanism is not well understood. Programmed death-ligand 1(PD-L1) plays a crucial role in inhibiting effector T cell function and is often up-regulated on tumor tissues with T cell infiltration. Here, Using relevant mouse tumor model, we confirmed that local RFA induced a sustained inflammatory response at a distant tumor but only resulted in a temporary tumor inhibition. In addition, we demonstrated that the nature of the inflammation of the distant tumor altered over time, from the initial strong CD8+ T cell-mediated immune responses to a later stage characterized by a loss of function for infiltrating CD8+ T cells, a concersion of Th1 to Th2 response, a shift to higher Treg to Teff ratios, and up-regulation of PD-1/PD-L1 expression. Moreover, we performed a retrospective case controlled study on patients with synchronous colorectal cancer liver metastases(CRCLM) who had received primary tumor resection with or without pre-operative RFA of their liver metastases. We found that RFA of liver metastases increased T cell infiltration but also PD-L1 expression in primary tumor. Further, we determined that combined therapy with RFA and anti-PD-1 antibody significantly enhanced T cell response, prevented conversion of Teff to Treg and inhibited proliferation of myeloid-derived suppressor cells(MDSC), resulting in a synergistic rejection of the distant tumor and a prolonged survival in mice model. These findings reveal the mechanism by which tumors inhibit the RFA efficacy and provide a strong rationale for exploring the potential of anti-PD-1 therapy in combination with RFA in the clinical setting.