Abstract
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8+ T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG-Stat3 siRNA enhanced CD8+ T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.