Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Abstract

Purpose Radiotherapy (RT) can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that RT-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell pro-apoptotic activities. Experimental Design Matched Gal-1 wildtype or null mice were implanted with Lewis Lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably down-regulated. 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. Thiodigalatoside (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 down-regulation. Lymphocyte counts, survival and plasma Gal-1 were analyzed in cohorts of RT-treated lung (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 TDG ablated RT-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 to controls. Similar observations were made after TDG treatment. RT-induced lymphopenia was associated with poorer overall survival in NSCLC patients treated with hypofractionated RT. Plasma Gal-1 increased while T-cell decreased after radiation in another group of patients. Conclusions RT-related systemic lymphopenia appeared to be mediated by RT-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis.

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