Liangrong Shi^1,2,3, Lujun Chen^1,3, Changping Wu^1,2,3,*, Yibei Zhu⁴, Bin Xu^1,3, Xiao Zheng^1,3, Mingfen Sun^1,3, Wen Wen⁴, Xichao Dai^1,2,3, Min Yang^1,2,3,4,Quansheng Lv⁴, Binfeng Lu^5,*, and Jingting Jiang^1,3,*

Author Affiliations

¹Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China.

↵*Corresponding Authors:
Binfeng Lu, University of Pittsburgh, 200 Lothrop Street, E1047, Pittsburgh, PA 15213. Phone: 412-648-9339; Fax: 412-648-9339; E-mail: binfeng@pitt.edu; Changping Wu, The Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China,wcpjjt@163.com; and Jingting Jiang, Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China,jiangjingting@suda.edu.cn

L. Shi and L. Chen contributed equally to this article.

Abstract

Purpose: Radio frequency 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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. Clin Cancer Res; 22(5); 1173–84. ©2016 AACR.

The copyright reseverd by Cancer Res; 22(5); 1173–84. ©2016 AACR. Please log on Cancer Res to view the full text.  http://clincancerres.aacrjournals.org/content/22/5/1173.abstract