PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells

Abstract

The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8 + T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8 + T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8 + T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer.

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity

“…PD-1 blockade has been used in combination with various therapeutic agents to improve immunotherapeutic effects, such as another immunosuppressive blocking antibody cytotoxic Tlymphocyte antigen-4 (CTLA-4) mAb, 14 the immune stimulating factor IL-2, 35 the blocking antibody of human epidermal growth factor receptor-2 (HER-2 / ErbB-2), 36 and radiotherapy. 37,38 In this study, we have explored two strategies to improve therapeutic efficacy of the high-profile PD-1 blocking mAb treatment and the potential side effects associated with PD-1 blockade: (a) an alginate hydrogel delivery system to deliver therapeutic agents to tumor local regions; (b) in combination with celecoxib.…”

CD8 + T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

“…An understanding of how to rescue exhausted CD8 ϩ T cells may be critical to decreasing the incidence of reactivation and reinfection, even after vaccination. By blocking PD-1-mediated inhibitory signals and supplementation with additional IL-2, others reported that exhaustion is a reversible phenotype of CD8 ϩ T cells (26,(35)(36)(37). For instance, a decrease in the production of reactive oxygen intermediates by macrophages mediated by PD-1-bearing CD4 ϩ and CD8 ϩ T cells allows increased intracellular pathogen load in leishmaniasis.…”

Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

“…Similarly, administration of low-dose IL-2 combined with PD-L1 blockade has been demonstrated to decrease inhibitory receptor expression and viral load in a chronic murine LCMV model as IL-2 treatment may foster the generation of a pool of CD44 hi PD-1 int T-cells that are more responsive to PD-L1 blockade. 49 Thus, novel therapeutic strategies, exploring the generation of more PD-1 neg and PD-1 int cells, instead of PD-1 hi cells to increase the susceptibility to PD-1/PD-L1 blockade, are clearly needed.…”