Reversal of Tumor Immune Inhibition Using a Chimeric Cytokine Receptor |
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Authors: | Ann M Leen Sujita Sukumaran Norihiro Watanabe Somala Mohammed Jacqueline Keirnan Ryu Yanagisawa Usanarat Anurathapan David Rendon Helen E Heslop Cliona M Rooney Malcolm K Brenner Juan F Vera |
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Affiliation: | 1.Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children''s Hospital and Houston Methodist Hospital, Houston, Texas, USA;2.Baylor College of Medicine, Texas Children''s Hospital and Houston Methodist Hospital, Houston, Texas, USA |
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Abstract: | The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation. |
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