This suggests that IL-2 administration may result in the generation of a pool of CD8 T cells that are more responsive to PD-L1 blockade. combining IL-2 treatment with blockade of the PD-1 inhibitory pathway experienced striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral weight. Interestingly, this reduction in viral weight occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits concern as a regimen for treating human chronic infections and cancer. Introduction CD8 T cells play a key role in eliminating and intracellular infections and SEP-0372814 tumors. However, in the setting of chronic antigen activation, such as that seen in chronic infections and tumors, CD8 T cells undergo exhaustion, causing them to become dysfunctional. SEP-0372814 This exhaustion WNT6 is usually characterized by decreased proliferative capacity, loss of cytokine secretion, reduced cytotoxic killing abilities, and phenotypic changes, including low expression of canonical memory markers, such as the IL-7 receptor chain (CD127), and also an increase in inhibitory receptors (1C3). While multiple mechanisms contribute to the process of exhaustion, the inhibitory receptor programmed cell death 1 (PD-1) has emerged as a major player in this process. PD-1 is the most well-characterized inhibitory molecule upregulated during chronic antigen activation and is associated with disease progression and immune dysfunction (2). Importantly, recent data from 2 clinical trials have highlighted the role of PD-1 inhibition in human cancers and have shown that PD-1 blockade, by in vivo administration of humanized antiCPD-1 or antiCPD-1 ligand 1 (antiCPD-L1) antibodies, is an effective immunotherapeutic for increasing tumor clearance. Notably, in vivo PD-1 blockade resulted in durable tumor reduction or clearance in multiple cancers, including lung malignancy, SEP-0372814 which is highly refractory to any treatment (4C6). These data correspond well with previous in vitro and in vivo animal model data showing that SEP-0372814 PD-1 plays a central role in T cell dysfunction during chronic infections and cancer and that PD-1 blockade can restore T cell function (2, 3, 7C16). Overall, these data indicate that PD-1 may be an important immunotherapeutic for cancers and chronic infections and signify that it is vital to find ways to increase the efficacy of PD-1 blockade. Multiple inhibitory mechanisms regulate CD8 T cell exhaustion, and, thus, combining PD-1 blockade along with other therapies, such as simultaneous blockade of multiple inhibitory receptors or therapeutic vaccination, results in enhanced reduction of viral loads and increased CD8 T cell responses in animal models of chronic infection. However, it is important to note that this mechanisms underlying the synergy of combined treatments has not been well explored (17C19). Overall, this suggests that combining strategies or treatments to combat chronic infections and cancer may be a valid strategy to increase efficacy. IL-2 is usually a cytokine that has a pleiotropic effect on multiple immune cell types and has been used as a therapy for several human diseases/conditions. IL-2 has been used to augment T cell responses against computer virus or tumor antigens in HIV and patients with metastatic malignancy. While high-dose intermittent IL-2 therapy has increased long-term survival for some patients with metastatic renal cell carcinoma (20) and IL-2 therapy alone or in combination with a peptide vaccine has resulted in clinical improvement for patients with metastatic melanoma (21, 22), it has shown very limited success when given during chronic human viral infections, such as when it is combined with antiretroviral drugs during HIV (23C28). Greater improvement was seen in one trial, with IL-2 administration combined with antiretroviral drugs and therapeutic vaccination during HIV contamination (29), although other small studies suggest that a long-term effect is not seen after antiviral therapy is usually discontinued (30C32). However, continuous IL-2 administration, along with therapeutic vaccination and antiretroviral treatment, in macaques infected with chronic SIV increases SIV-specific CD8 T cell responses and results in decreased viral burden (33, 34). Overall, a major limitation of high-dose intermittent IL-2 therapy is usually that it can result in severe toxicity issues, such as vascular leakage. By comparison, daily, much lower doses of IL-2 can ameliorate these toxicity issues (35). Recently encouraging human data show that daily low-dose IL-2 therapy may be useful for increasing Treg figures and reducing autoimmune complications in patients with graft-versus-host disease as a result of undergoing an allogeneic hematopoietic stem cell transplantation (36) and also in patients with hepatitis CCinduced vasculitis (37). Importantly, these recent studies indicate that daily low-dose IL-2 therapy is usually well tolerated by patients (36, 37). While daily low-dose IL-2 therapy increases Tregs in the context SEP-0372814 of autoimmune complications, in contrast, our laboratory has shown.