An Optogenetic Controllable T Cell System for Hepatocellular Carcinoma Immunotherapy

Abstract

<b>Rationale:</b> T-cell based immunotherapy increasingly shows broad application prospects in cancer treatment, but its performance in solid tumors is far from our expectation, partly due to the re-inhibition of infiltrated T cells by immunosuppressive tumor microenvironment. Here we presented an artificial synthetic optogenetic circuit to control the immune responses of engineered T cells on demand for promoting and enhancing the therapeutic efficiency of cancer immunotherapy. <b>Methods:</b> We designed and synthesized blue-light inducible artificial immune signaling circuit and transgene expression system. The blue light triggered transgene expression was investigated by luciferase activity assay, qPCR and ELISA. The <i>in vitro</i> cytotoxicity and proliferation assays were carried out on engineered T cells. The <i>in vivo</i> anti-tumor activity of engineered T cells was investigated on xenograft model of human hepatocellular carcinoma. <b>Results:</b> Blue light stimulation could spatiotemporally control gene expression of specific cytokines (IL2, IL15, and TNF-α) in both engineered 293T cells and human primary T cells. This optogenetic engineering strategy significantly enhanced the expansion ability and cytolytic activity of primary T cells upon light irradiation, and the light activated T cells showed high-efficiency of elimination against xenograft of hepatocellular carcinoma cells. <b>Conclusions:</b> The current study represented an engineered remotely control T cell system for solid tumor treatment, and provided a potential strategy to partially overcome the intrinsic shortages of current immune cell therapy.