Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Peiwen Kuo, Scott V Bratman, David B Shultz, Rie von Eyben, Cato Chan, Ziwei Wang, Carmen Say, Aparna Gupta, Bill W Loo Jr, Amato J Giaccia, Albert C Koong, Maximilian Diehn, Quynh-Thu Le
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 21 Pg. 5558-69 (Nov 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25189484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Galectin 1
• Thiogalactosides
• thiodigalactoside

Topics

• Animals
• Apoptosis (radiation effects)
• CD8-Positive T-Lymphocytes (metabolism)
• Carcinoma, Lewis Lung (metabolism, radiotherapy)
• Carcinoma, Non-Small-Cell Lung (metabolism, radiotherapy)
• Cell Line, Tumor
• Galectin 1 (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (metabolism, radiotherapy)
• Lymphopenia (metabolism)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (metabolism)
• Thiogalactosides (pharmacology)