Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21

摘要: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, design successful strategies requires deeper understanding mechanisms underpinning CVA21 efficacy, particular, role anti-tumor immunity. Therefore, this study aimed to examine ability induce human immunity, identify cellular mechanism responsible. This utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, iii) patients taking part STORM trial, who received intravenous CVA21; receiving were consented separately accordance local institutional ethics review approval. Collectively, these samples used characterize development innate adaptive responses following treatment. An Initial characterization cells, collected cancer infusion CVA21, confirmed that activated effector patients. Next, using hematological models which sensitive (Multiple Myeloma; MM) or resistant CVA21-direct oncolysis, we demonstrated stimulated potent responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cytotoxicity; 3) priming tumor-specific cytotoxic T lymphocytes, specificity towards known tumor-associated antigens. Importantly, immune-mediated killing both MM AML, despite AML was observed. Upon further examination responsible for CVA21-induced immunity have identified importance type I IFN NK cell activation, ICAM-1 plasmacytoid dendritic key mediators response. work supports an immunotherapeutic treatment MM. Additionally, data presented provides important insight into CVA21-mediated immunotherapy aid biomarkers predict response rationalize future drug combinations.