Abstract 384: Role of PD-L1 immunoregulatory protein in breast cancer cells metabolic reprogramming

Abstract

Abstract When evolving to a neoplastic state, normal cells acquire many characteristics; indeed, tumor cells follow abnormal metabolic pathways and exhibit the ability to avoid immune destruction, partly by exploiting immune checkpoints. Many of these are currently under clinical investigation for new cancer treatments, notably the PD-1/PD-L1 axis. Programmed Death-Ligand 1 (PD-L1) molecule belongs to the B7 immunoregulatory proteins family and was originally described as mediating tumor immuno-escape through interaction with its receptor PD-1 on T cells. Associated with poor cancer outcome, aberrant PD-L1 expression has been observed in hematologic malignancies and in multiple solid tumor types. Interestingly, some reports highlight PD-L1 intrinsic effects in cancer cells. Actually, this protein has been shown to regulate tumor cell proliferation and resistance to chemotherapy through apoptosis inhibition, without interacting with PD-1. However, cellular mechanisms modulated by PD-L1 and involved in these functions are still unclear. Abnormal metabolic pathways are known for contributing to tumor growth and therapy resistance; therefore, in this study, we investigated the role of PD-L1 in cancer cell metabolic reprogramming. By using genome editing, we knocked-out the CD274 gene encoding PD-L1 in breast cancer cell line MDA-MB-231 and investigated metabolic functions after PD-L1 overexpression in the same cells. We observed that PD-L1 induces a shift from oxidative phosphorylation to glycolysis, indicating this molecule promotes the Warburg effect in these tumor cells. Moreover, in agreement with an increasing mitochondrial reactive oxygen species (ROS) production, transcriptomic study suggested that PD-L1 represses Nrf2-mediated oxidative stress response pathway, especially NQO2, GSTM3 and ABCC2 genes. Additionally, in silico analysis of breast cancer patients databases highlighted a correlation between CD274 gene and oxidative stress gene signature (GSTM3; CYBB) or glucose transporters genes (SLC2A1; SLC2A3) expressions. Besides, glucose is mostly used by cancer cells to favor biosynthesis of diverse biomolecules required for cellular proliferation; assuming that PD-L1 overexpression modulates glycolytic capacities of MDA-MB-231 cells, we are performing a metabolomic study to determine the impact of this protein on the diverse biosynthetic outputs linked to glucose metabolism. The above results could explain our human breast cancer cells xenograft experiments in NUDE mice demonstrating that PD-L1 increases tumoreginicity. Furthermore, to identify which protein domain is implicated in these metabolic functions, experiments on PD-L1 mutant forms are ongoing. Thus, our study evidences novel PD-L1 intrinsic tumor-promoting functions, suggesting that therapeutic agents inhibiting these mechanisms would be promising for breast cancer treatment. Citation Format: Julie Berthe, Jérôme Kluza, Hassiba El Bouazzati, Isabelle Briche, Xavier Thuru, Sylvie Aliegue-Zouitina, Bruno Quesnel. Role of PD-L1 immunoregulatory protein in breast cancer cells metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 384.