Abstract 5126: Modulation of lactate in the tumor microenvironment with lactate transporter inhibitor in a melanoma syngeneic mouse model

Abstract

Abstract Solid tumors often have altered metabolism that depend on aerobic glycolysis for energy and macromolecules for cell survival thereby generating lactate as a metabolic byproduct. Lactate is transported across the cell membrane into tumor microenvironment (TME) using monocarboxylate transporters, MCT1 and MCT4. MCTs facilitate proton linked transport of monocarboxylate molecules such as lactate, pyruvate, and ketone bodies across the plasma membrane. Lactate released by glycolytic cells into the TME results in a metabolic symbiosis when other tumor cells utilize lactate as an energy source that undergo oxidative metabolism which is referred to as “lactate shuttle”. Moreover, lactate induces inhibitory pathways on immune cells, especially on cytotoxic CD8+ T-cells resulting in local immunosuppression in the TME. Additionally, acidosis of TME through lactate results in local inflammation and angiogenesis by activation of VEGFR signaling. The net result of an increased lactate in TME is that it generates a conducive milieu for tumor growth and metastasis. Although studies show that MCT inhibitors mitigate the effects of lactate and promote immune function, its effect on immune cells in the context of tumor infiltration is yet to be explored. In this study, we used a MCT inhibitor NGY-A to determine the effect of suppressing lactate levels in the TME and restoring the anti-tumor immunity. In our preliminary studies to determine the cytotoxicity, NGY-A showed significant cancer cell killing in multiple cell lines in vitro. To determine the in vivo effect of NGY-A, syngeneic mouse model of SM1 melanoma cells harboring BRAF mutation in C57BL/6 mice was studied. When treated with NGY-A (10 mg/kg, i.p injection) (n=15), a significant decrease in tumor volumes was observed compared to controls (n=15). Gene expression analysis of total RNA isolated from SM1 tumors by quantitative RT-PCR indicated that expression of immunosuppressive molecules such as Cd274 (PD-L1), Cd276 (B7-H3) and Lgals9 (Galactin-9) was down regulated in NGY-A (n=5) treated tumors compared to the control tumors (n=5). An increase in IFN-γ (IFNG) gene expression in NGY-A treated samples indicated an increase in CD8+ T-cell tumor infiltration. Future studies would include analysis of phenotype of tumor infiltrating immune cells and cytokine profiles after treatment with NGY-A in combination with immune checkpoint blockade inhibitors which could potentially be an effective strategy to treat melanoma. Citation Format: Satish Kumar Reddy Noonepalle, Jennifer Kim, Melissa Hadley, Erica Palmer, Debarati Banik, Tessa Knox, Sophiya Ephrame, Prathima Vembu, Summer Rudish, Sara Moufarrij, Jaime Escobedo, Vincent Sandanayaka, Alejandro Villagra. Modulation of lactate in the tumor microenvironment with lactate transporter inhibitor in a melanoma syngeneic mouse model [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 5126.