PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor.

Abstract

Radiofrequency ablation (RFA) has been shown to elicit tumor-specific T-cell immune responses, but is not sufficient to prevent cancer progression. Here, we investigated immune-suppressive mechanisms limiting the efficacy of RFA. We performed a retrospective case-controlled study on patients with synchronous colorectal cancer liver metastases who had received primary tumor resection with or without preoperative RFA for liver metastases. Tumor-infiltrating T cells and tumoral PD-L1 expression in human colorectal cancer tissues were analyzed by immunohistochemistry. T-cell immune responses and PD-1/PD-L1 expression were also characterized in an RFA mouse model. In addition, the combined effect of RAF and PD-1 blockade was evaluated in the mouse RFA model. We found that RFA treatment of liver metastases increased not only T-cell infiltration, but also PD-L1 expression in primary human colorectal tumors. Using mouse tumor models, we demonstrated that RFA treatment of one tumor initially enhanced a strong T-cell-mediated immune response in tumor. Nevertheless, tumor quickly overcame the immune responses by inhibiting the function of CD8(+) and CD4(+) T cells, driving a shift to higher regulatory T-cell to Teff ratio, and upregulating PD-L1/PD-1 expression. Furthermore, we established that the combined therapy of RFA and anti-PD-1 antibodies significantly enhanced T-cell immune responses, resulting in stronger antitumor immunity and prolonged survival. The PD-L1-PD-1 axis plays a critical role in dampening RFA-induced antitumor immune responses, and this study provides a strong rationale for combining RFA and the PD-L1/PD-1 blockade in the clinical setting.