Data from PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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<sup>+</sup> and CD4<sup>+</sup> 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(5); 1173–84. ©2016 AACR</i>.</p></div>

Cathepsin C promotes colorectal cancer metastasis by regulating immune escape through upregulating CSF1

“…As a result, combined techniques to improve CRC therapy effectiveness have become critical. Anti-PD-1/ anti-PD-L1 combined with anti-CTLA4 drugs, locoregional treatments, or VEGF/VEGFR inhibitors, for example, boosts anti-tumor immunity synergistically [31][32][33]. These findings suggested that anticancer drugs that stimulate tumor immunity, when combined with anti-PD-1/anti-PD-L1 antibodies, might provide show encouraging effects.…”