TUMOR AND IMMUNO-METABOLISM BASED LACTATE TRANSPORTER INHIBITOR FOR METASTATIC MELANOMA Abstract Immunotherapy area for cancer is rapidly expanding with the discovery of new targets and methods to activate immune function within tumors. However, immunotherapy has been successful so far only subset of metastatic patients. Metastatic melanoma is highly heterogeneous cancer and lack of response to current treatments is largely due to high heterogeneity in the tumor microenvironment (TME) of melanoma. Lactate-rich TME has been shown as highly immunosuppressive and promotes tumor growth and progression. Cancer cells transport lactate across the cell membrane to the extracellular matrix via monocarboxylate transporters, MCT1 and MCT4. We have developed dual MCT1/4 inhibitors (dMCTis) to block lactate excretion to the TME thereby directly killing cancer cells and simultaneously activating local immunity in the TME. In our preliminary studies, we have shown that dMCTis are potent compounds against multiple melanoma cell lines in vitro. Also, we have shown that in in vivo experiments with both xenograft model (MDA-MB-231, breast cancer) and syngeneic mouse models of melanoma; B16-F10 (BRAFWT) and SM1 (BRAFV600E), MCT1/4 inhibitors exert significant anti-tumor efficacy. Anti-tumor efficacy in MDA-MB-231 immune-deficient xenograft model shows inhibitorsâ direct cell killing effect. In the SM1 syngeneic model, we observed a decrease in expression of multiple immunosuppressive molecules such as B7 family proteins in treated tumors compared to the control tumors. Furthermore, profiling of cytokines indicated an increase in pro-inflammatory IFNγ, TNFα, IL-1β and decrease in tumor promoting TGFβ, IL-10 in treated tumors compared to the control tumors confirming that the anti-tumor effect of dMCTis is in part due to enhanced immune function. This was further corroborated by the immune only efficacy of the compound in B16-F10 model indicating the immune component of these compounds. Supported by the preliminary data, we hypothesize that blocking the lactate shuttle with MCT inhibitor will reprogram the metabolic landscape of tumor microenvironment in melanoma by suppressing the tumor growth and enhancing the immune surveillance, thereby promoting the efficacy of these inhibitors as a single agent or in combination with immune check point inhibitors in metastatic melanoma. To test our hypothesis, we propose the following specific aims: (1) To study in vitro effects and mechanisms of dMCTi inhibitor, NGY-B in representative melanoma cell lines, (2) To investigate the efficacy and immune activation power of NGY-B in immune-deficient A375 mouse xenograft model, (3) To evaluate in vivo effects of NGY-B as a single agent and in combination with immune checkpoint inhibitors in immune-competent SM1 and B16-F10-metastatic mouse models. The proposed work will determine the feasibility of dMCTis as novel immunotherapeutic agents to treat metastatic melanoma. We anticipate that the proposed study will enhance our understanding of the role of lactate on local TME, and its effect on the composition and function of infiltrating immune cells to develop novel immunotherapeutic combinations to treat metastatic melanoma.
Public Health Relevance Statement: Project Narrative Metastatic melanoma is a critically unmet medical need, and 5-year survival rate is <20% even with current immunotherapy. There are no good therapies to treat metastatic melanoma. The current proposal aims to enhance our understanding of the role of novel lactate transporter inhibitors and tumor-derived lactate in shaping the local tumor microenvironment and metabolic profile of tumor cells and immune cells in melanoma. Lactate transporter inhibitors will not only suppress the tumor growth but also enhances the local immune function. The proposed study is of high relevance to the public health in advancing novel approaches to target cancer cell metabolic pathways that will impair cancer cell survival while enhancing the endogenous anti- tumor immunity. Upon completion of the study, metastatic melanoma patients would significantly benefit from the proposed single agent or combination therapy with lactate transport inhibitors and immune check point inhibitors.
Project Terms: Adopted; Amino Acids; Anti-inflammatory; antitumor effect; Area; Arginine; base; cancer cell; Cell Culture System; cell killing; Cell Line; Cell membrane; Cell Survival; Cells; chemokine; combinatorial; Combined Modality Therapy; cytokine; Data; Dose; effector T cell; Excretory function; experimental study; Extracellular Matrix; Future; Glycolysis; Granzyme; Heterogeneity; Human; humanized mouse; Immune; immune activation; immune checkpoint blockade; Immune checkpoint inhibitor; immune function; Immunity; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; in vivo; Inflammatory; inhibitor/antagonist; Interferon Type II; Interleukin-1 beta; Interleukin-10; Lactate Transporter; Lead; macrophage; malignant breast neoplasm; Malignant Neoplasms; MDA MB 231; Measures; Mediating; Medical; melanoma; Melanoma Cell; Metabolic; Metabolic Pathway; metabolic profile; Metabolism; Metastatic Melanoma; Methods; Modeling; Molecular; Mouse Cell Line; mouse model; Mus; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; neoplastic cell; novel; novel strategies; Patient-Focused Outcomes; Patients; perforin; Pharmaceutical Preparations; Phenotype; Production; Protein Family; Public Health; Regimen; response; Role; Schedule; Shapes; Signal Pathway; small molecule; Surface; Survival Rate; T-Cell Activation; Techniques; Testing; Therapeutic; TNF gene; Transforming Growth Factor beta; transport inhibitor; treatment effect; tumor; tumor growth; tumor heterogeneity; Tumor Immunity; tumor microenvironment; tumor progression; Tumor Tissue; Tumor-Derived; Tumor-infiltrating immune cells; Work; Xenograft
