The metabolic basis of resistance to Adoptive T Cell Therapy (ACT) in patients with solid tumors

Abstract

Abstract Adoptive T cell therapy (ACT) has produced impressive responses in a subset of patients with advanced malignancies. However, majority of patients still failed to respond. Thus, there is an urgent need to understand the resistant mechanisms in non-responders and develop more effective ACT strategies. Here, we employed two independent and unbiased approaches to identify novel molecular determinants of immune resistance. We generated gene expression profiles on an immune resistant melanoma cell line to identify alternative immunosuppressive mechanisms. In addition, we utilized a new high-throughput shRNA screening platform developed by our group to functionally interrogate immune resistance in patient-derived melanoma cells. Results from both analyses implicated tumor-associated glycolysis as a critical pathway that enables tumor cells to evade T cell-mediated antitumor activity. By using samples from melanoma and non-small cell lung cancer patients, we showed that increased expression of glycolysis-related genes is associated with poor T cell infiltration of tumors. Moreover, we found that increasing tumor glycolysis impaired T cell killing of melanoma cells, while inhibiting glycolysis restored T cell-mediated apoptosis of tumor cells. More importantly, from two non-overlapping ACT-treated patient cohorts, we discovered that tumor glycolytic activity in patients who experienced disease progression following ACT was significantly higher compared to those patients who were responsive to therapy. Taken together, our results demonstrate that tumor glycolytic metabolism is associated with the efficacy of ACT and identify glycolysis as a candidate target for combinatorial therapeutic intervention.