dual anti-ox40il-2 therapy augments tumor immunotherapy via il-2r-mediated regulation of ox40 expression双重anti-ox40il-2疗法增强肿瘤免疫治疗通过il-2r-mediated ox40表达的调节.pdfVIP

Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression 1 1,2 1 1,2 William L. Redmond *, Todd Triplett , Kevin Floyd , Andrew D. Weinberg 1 Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, United States of America, 2 Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, Oregon, United States of America Abstract The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not ¨ expressed on naıve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well- established (.5 wks) tumors, leading to increa