Immunomodulation of the Tumor Microenvironment by Tumor-Derived Metabolites: Development of Orally Bioavailable Small Molecules for Cancer Immunotherapy
Vincent Sandanayaka1*, Ronald Blasberg2, Taha Merghou2, Alejandro Villagra3, Ana Lepique4, Ivan Cohen2, Jayakumar Nair3; Simone Stone4, Jaime Escobedo1
1Nirogyone Therapeutics Inc., Cambridge, MA, USA; 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3George Washington University, Washington, DC, USA; 4Universidade de São Paulo, São Paulo, Brazil
The majority of tumors consume high amount of glucose and excrete large amount of lactate to the tumor microenvironment (TME). Recent studies have demonstrated that lactate acts as a strong immunosuppressor in the TME hampering anti-tumor immunity response. Additionally, lactate acts as an alternative bioenergetic molecule for cancer cell survival in a typical glucose-depleted TME. Genetic and pharmacological intervention of lactate accumulation in the TME have shown that the immune system could be activated leading to significant cancer cell killing in vitro and tumor growth reduction in vivo. We set out to study this concept by targeting a set of novel validated target class monocarboxylate transporters (MCTs) that lower lactate level. MCT1 and MCT4 are plasma membrane-bound proteins that exclusively transport lactate produced by malignant cells. We identified two novel chemically distinct small molecule series that block these transporters. We have shown that these molecules not only can activate immune system but also directly kill cancer cells. This one-two punch strategy against tumors would be an innovative approach to overcome the deficiencies of the current immunotherapy strategies. We will present preliminary results of these compounds both in vitro and in vivo showing lactate reduction, direct cancer cell killing, immune activation through multiple immune cells including T-cells and macrophages, and tumor growth inhibition.