A “2 + 2” strategy for tumor immune microenvironment remodeling based on complementary immune checkpoint blockade

Abstract

Despite a clinical success of cancer immunotherapy, its efficacy is often limited due to immune resistance and insufficient immune response induced by the tumor immune microenvironment (TIME). Thus, further appropriate interventions are needed to reshape the TIME and to maintain an effective and durable immune response. Herein, we report that a strategy involving complementary immune checkpoint blockade of ADAR1 and PD-1 can enhance the immune response and decrease the rate of immune evasion by regulating the TIME. We first designed a charge-reversible nanosystem Au-PEI/shADAR1/PEI-citraconic anhydride (AAPC), to effectively deliver shADAR1 to inhibit expression of ADAR1, a potential immune checkpoint in tumor cells. Then, we demonstrated a simultaneous decrease in immune escape and activation of antitumor immunity in tumor-bearing mice upon combined treatment with AAPC and an anti-PD-1 antibody. The immune checkpoint blockade acts on T cells and we show that this combination therapy was more efficacious than individual treatments. Additionally, mechanistic and transcriptomic analysis confirmed that complementary immune checkpoint blockade regulated the abundance of immune cells. Finally, combined with X-ray irradiation, a “2 + 2” strategy involving combined dual normalization (“2”, dsRNA sensitization and anti-PD therapy) and dual enhancement (“2”, antigen presentation by radiotherapy and immunogenetic cell death induced by MDA5 activation) immunotherapy efficiently reshaped the TIME by regulating a variety of immune cells.