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Combinational immunotherapy of anti-OX40 antibody and IDO inhibitor synergistically enhances anti-tumor immune T cell-mediated responseOne of the major goals of cancer immunotherapy is to disrupt the immunosuppressive environment that allows tumors to thrive in and to generate potent and enduring antitumor specific-immune responses. Cancer vaccines may elicit antigen-specific immune responses; however, this is, in many tumor models and in human cancer, insufficient for positive outcomes due to existence of multiple immune-inhibitory mechanisms in tumors. A relatively recently introduced strategy to increase the therapeutic efficacy of tumor vaccination is to combine different immunological approaches that target different immunosuppressive pathways and to enhance the efficacy of vaccines by T cell agonists. OX40 is a co-stimulatory receptor expressed on T cells that can lead to proliferation and enhancement ofT cell effector function when bound by its ligand or targeted with agonist antibody. Here, we show that different doses of anti-OX40 antibody (Ab) elicit differential impacts on the T cell immune response resulting in either efficacious or detrimental therapeutic effect in immunized tumor-bearing mice. We demonstrate that treating tumor-bearing mice with an optimal dose of 1 mg/kg anti-OX40 Ab leads to a potent therapeutic and immune anti-tumor effect when combined with vaccine, whereas higher dose at 2.5 mg/kg of anti-OX40 Ab with vaccine increases the accumulation of regulatory T cells in the tumor and diminishes the therapeutic effect. Furthermore, we proposed that OX40 downstream molecular signaling through AKT activation in T cells may elucidate the differential T cell response when stimulated with anti-OX40 Ab. After optimizing the dose of agonist anti-OX40 Ab to stimulate the immune system toward maximal anti-tumor response when combined with vaccine, we strategized to improve the combinational therapy by targeting the so far untouched immunosuppressive environment. One of the immune suppressive molecules correlating with cancer progression is indoleamine-(2,3)-dioxygenase (IDO) enzyme. The catalytic activity of IDO hinders effector T cells from properly eliciting an anti-tumor effect. Here, we further evaluated the therapeutic outcome and immune mechanisms of the vaccineinduced immune response enhancement by agonist anti-OX40 antibody, while inhibiting the immunosuppressive IDO enzyme. We demonstrate that therapeutic efficacy of this combinational treatment leads to a profound inhibition of tumor growth and complete regression of established tumors in 60% of treated mice. We show that the mechanisms responsible for this therapeutic potency are: i) an increase in vaccine-induced tumorinfiltrating effector T cells that is facilitated by anti-OX40 antibody, and ii) a decrease of IDO enzyme activity within the tumor and the enhancement in the functionality of effector T cells that are facilitated by 1-methyl tryptophan (1-MT, IDO inhibitor). Our findings provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.