Primary Human T Lymphocytes Engineered with a Codon-Optimized IL-15 Gene Resist Cytokine Withdrawal-Induced Apoptosis and Persist Long-Term in the Absence of Exogenous Cytokine

摘要

IL-15 is a common gamma-chain cytokine that has been shown to be more active than IL-2 in several murine cancer immunotherapy models.Although T lymphocytes do not produce IL-15,murine lymphocytes carrying an IL-15 transgene demonstrated superior antitumor activity in the immunotherapy of B16 melanoma.Thus,we sought to investigate the biological impact of constitutive IL-15 expression by human lymphocytes.In this report we describe the generation of a retroviral vector encoding a codon-optimized IL-15 gene.Alternate codon usage significantly enhanced the translational efficiency of this tightly regulated gene in retroviral vector-transduced cells.Activated human CD4~+ and CD8~+ human lymphocytes expressed IL-15Ralpha and produced high levels of cytokine upon retroviral transduction with the IL-15 vector.IL-15-transduced lymphocytes remained viable for up to 180 days in the absence of exogenous cytokine.IL-15 vector-transduced T cells showed continued proliferation after cytokine with-drawal and resistance to apoptosis while retaining specific Ag recognition.In the setting of adoptive cell transfer,IL-15-transduced lymphocytes may prolong lymphocyte survival in vivo and could potentially enhance antitumor activity.