Significance Granzymes are serine proteases released by cytotoxic lymphocytes and induce cell death in virus-infected cells and tumor cells. However, granzymes also exist extracellularly in the blood circulation of patients with autoimmune diseases and infections and may contribute to inflammation. Here, we show that human granzyme K (GrK) binds to Gram-negative bacteria and to lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component. Our data indicate that GrK lowers the threshold for monocyte activation by LPS, in that GrK synergistically increases LPS-induced release of proinflammatory cytokines in vitro and in vivo. In conclusion, GrK modulates the innate immune response against LPS and Gram-negative bacteria and may contribute to the pathogenesis of diseases associated with a local or systemic bacterial infection.

Reoviruses are non-enveloped viruses with a segmented double stranded RNA genome. In humans, they are not associated with serious disease. Human reoviruses exhibit an inherent preference to replicate in tumor cells, which makes them ideally suited for use in oncolytic virotherapies. Their use as anti-cancer agent has been evaluated in several clinical trials, which revealed that intra-tumoral and systemic delivery of reoviruses are well tolerated. Despite evidence of anti-tumor effects, the efficacy of reovirus in anti-cancer monotherapy needs to be further enhanced. The opportunity to treat both the primary tumor as well as metastases makes systemic delivery a preferred administration route. Several pre-clinical studies have been conducted to address the various hurdles connected to systemic delivery of reoviruses. The majority of those studies have been done in tumor-bearing immune-deficient murine models. This thwarts studies on the impact of the contribution of the immune system to the tumor cell eradication. This review focuses on key aspects of the reovirus/host-cell interactions and the methods that are available to modify the virus to alter these interactions. These aspects are discussed with a focus on improving the reovirus’ antitumor efficacy.

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Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs.

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