PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor
Liangrong Shi1,2,3, Lujun Chen1,3, Changping Wu1,2,3,*, Yibei Zhu4, Bin Xu1,3, Xiao Zheng1,3, Mingfen Sun1,3, Wen Wen4, Xichao Dai1,2,3, Min Yang1,2,3,4,Quansheng Lv4, Binfeng Lu5,*, and Jingting Jiang1,3,*
1Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China.2Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China.
3Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China.
4Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Jiangsu Suzhou, China.
5Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Binfeng Lu, University of Pittsburgh, 200 Lothrop Street, E1047, Pittsburgh, PA 15213. Phone: 412-648-9339; Fax: 412-648-9339; E-mail: firstname.lastname@example.org; Changping Wu, The Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China,email@example.com; and Jingting Jiang, Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China,firstname.lastname@example.org
L. Shi and L. Chen contributed equally to this article.
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