title: PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Liangrong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Lujun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Changping
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Jiangsu Suzhou, China.
authors.forename: Yibei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Mingfen
authors.initials: M
authors.lastname: Sun
authors.affiliation: Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Jiangsu Suzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Xichao
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.|Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Jiangsu Suzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, Jiangsu Suzhou, China.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Department of Immunology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Tumor Biological Treatment, Soochow University, Changzhou 213003, Jiangsu, China.|Jiangsu Engineering Research Center for tumor Immunotherapy, Changzhou 213003, Jiangsu, China.
authors.forename: Jingting
authors.initials: J
authors.lastname: Jiang
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017115:Catheter Ablation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy* / Q000556:secondary; D008297:Male; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor