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A schematic of tumor/host combinations showing Gal-1 WT and null C57Bl6/mice subcutaneous injection with Wt and shGal-1 LLC1 cells, time line of cell injection, tumor irradiation and blood collection time points. The relative plasma Gal-1 levels for each treatment group is also shown.

Supplementary materials and methods and figure legends from Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Gal-1 inhibition increases tumor radiation response in vitro and in vivo.

Supplementary Table 1. Patient characteristics of 20 NSCLC patient receiving SABR. Supplementary Table 2. Patient characteristics of 24 HNSCC patients receiving radiation with cetuximab or cisplatin.

Tumor irradiation effect on T lymphocytes, common lymphoid progenitor cells (CLPs) and Gal-1 expression in bone marrow cells.

Radiation-related lymphopenia is associated with worse distant, local and regional progression free survival in NSCLC, in similar between radiation and cetuximab or cisplatin treated HNSCC and its severity trends with relapse in HNSCC. A higher rise in plasma Gal-1 was also seen with relapse.

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. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.

Increases in gal-1 secretion after tumor cell irradiation in vitro.

Lymphocytes from Gal-1 WT and null mice exhibiting similar sensitivity to ionizing radiation and recombinant Gal-1.