Abstract 547: Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer

Abstract

Abstract Apart from the cytotoxic effect of radiation- or chemotherapy it has become evident that these treatments are able to induce an immune response which can play an additional and pivotal role in clearing tumours. This treatment-induced immunogenic tumour cell death (ICD) enables the host's immune system to recruit to the tumour and recognise and kill tumour cells which can even extend to yet untreated metastases, a phenomenon called “abscopal effect”. For the first time, we found evidence that radiation and/or chemo-treatment stimulates a pronounced up-regulation of both, PD-L1 and Galectin-9 on pre-apoptotic and apoptotic gastric tumour cells. Both these proteins exert immuno-modulatory signals which in turn may dampen the aimed immunogenicity of the treatment. PD-L1, which is the ligand to programmed cell death protein 1 (PD1) on T cells, and its upregulation is commonly used by cancer cells to evade immunity. PD-L1 causes T cell apoptosis and hence an inhibition of T cell driven anti-tumour immunity. Galectin-9 exerts immunoinhibitory functions and is, together with the immunostimulatory molecule HMGB1, a competitive binding partner for the receptor T-cell immunoglobulin domain and mucin domain 3 (Tim-3). Once engaged by its ligand, Tim-3 either exerts stimulatory or inhibitory effects, depending on ligand, cell type, maturation state and Tim-3 expression rate. Together with PD-L1, Galectin-9 enables a complex interplay between cancer cells and cells of the adaptive immune response expressing PD1 and Tim-3. Based on these results, we are investigating the mechanism responsible for PD-L1 and Galectin-9 upregulation and the effect on the efficacy of radio- as well as chemotherapy on tumour eradication. Additionally, due to their potentially enhancing effect on anti-tumour immunity, we are studying the therapeutic value of blocking Abs specific for human PD1 and/or Tim-3 in cancer immunotherapy. Citation Format: Sven H. Petersen. Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 547.