Combining an adenovirus encoding human endostatin and PD-1 blockade enhanced antitumor immune activity

Abstract

Treatment with immune checkpoint inhibitors (ICIs) has recently achieved unprecedented clinical benefits, becoming a critical treatment for patients with cancer. However, a set of patients are resistant to immune checkpoint inhibitor therapy, likely due to the limited presence or lack of tumor-infiltrating lymphocytes in their tumors. Increasing data indicate that antiangiogenic therapy substantially reduces cancer-induced immunosuppression and is an effective way to enhance the efficacy of cancer immunotherapies by combination with ICIs. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and programmed cell death-1 (PD-1) blockade dramatically abrogated tumor growth, inhibited microvessel density, and promoted tumor apoptosis, compared to treatment with the single agents. Further investigation using flow cytometry showed that combined therapy significantly increased CD8⁺ T-cell infiltration into tumors and promoted the level of CD8⁺ IFN-γ⁺ T cells. Moreover, combined therapy effectively reduced the frequencies of CD11b⁺ F4/80⁺ tumor-associated macrophages (TAMs) and slightly increased M1/M2 ratio in the tumors. RNA-seq analysis of tumor tissue following combined therapy also demonstrated upregulated expression of genes associated with the antitumor immune response. These data support the rationale for combining antiangiogenic and ICIs for cancer therapy.