TMET-21. ENHANCING THE METABOLIC FITNESS OF T CELLS TO TREAT BRAIN TUMORS

Abstract

Abstract INTRODUCTION Glioblastoma is a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. Objectives: The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating the glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred. METHODS The glucose metabolic pathway of T cells was modulated via overexpression of glucose transporters. The functionality of metabolically modified T cells was investigated in murine and human models. RESULTS We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provided a survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration and expansion of adoptively transferred T cells, resulting in improved survival. CONCLUSION This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.