title: Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice.
abstract: Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
authors: Chiao-Jung
authors: CJ
authors: Kao
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
authors: Gregory T
authors: GT
authors: Wurz
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
authors: Yi-Chen
authors: YC
authors: Lin
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
authors: Daniel P
authors: DP
authors: Vang
authors: Comparative Pathology Laboratory, UC Davis School of Veterinary Medicine, University of California, Davis, Davis, California.
authors: Stephen M
authors: SM
authors: Griffey
authors: ImmunoOncology, Merck Serono Research, Merck KGaA, Darmstadt, Germany.
authors: Michael
authors: M
authors: Wolf
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California. mwdegregorio@ucdavis.edu.
authors: Michael W
authors: MW
authors: DeGregorio
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000532:radiotherapy*; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000097:blood*; D016896:Treatment Outcome; D059016:Tumor Microenvironment; D014520:Urethane / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D035683:MicroRNAs; D014520:Urethane; D002945:Cisplatin