title: Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response.
abstract: OBJECTIVE
  Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.
  
  
  METHODS
  Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non-small cell lung cancer (NSCLC)] and head and neck cancer patients.
  
  
  RESULTS
  LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8(+) T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.
  
  
  CONCLUSIONS
  Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Kuo
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Scott V
authors.initials: SV
authors.lastname: Bratman
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: David B
authors.initials: DB
authors.lastname: Shultz
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Rie
authors.initials: R
authors.lastname: von Eyben
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Cato
authors.initials: C
authors.lastname: Chan
authors.affiliation: University of California, San Diego School of Medicine, La Jolla, California.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Carmen
authors.initials: C
authors.lastname: Say
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Aparna
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Bill W
authors.initials: BW
authors.lastname: Loo
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Diehn
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California. qle@stanford.edu.
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000532:radiotherapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D037483:Galectin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D008231:Lymphopenia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism; D013862:Thiogalactosides / Q000494:pharmacology
chemical_list: D037483:Galectin 1; D013862:Thiogalactosides; C031803:thiodigalactoside