Cytotoxic and immune‐mediated killing of human colorectal cancer by reovirus‐loaded blood and liver mononuclear cells

• Published in: International journal of cancer Vol. 132; no. 10; pp. 2327 - 2338
• Main Authors: Adair, Robert A., Scott, Karen J., Fraser, Sheila, Errington‐Mais, Fiona, Pandha, Hardev, Coffey, Matt, Selby, Peter, Cook, Graham P., Vile, Richard, Harrington, Kevin J., Toogood, Giles, Melcher, Alan A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.05.2013; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - pathology; Antibodies; Biological and medical sciences; Blood; Blood - immunology; Cancer; Cell Line, Tumor; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; colorectal liver metastases; Colorectal Neoplasms - immunology; Cytotoxicity; Cytotoxicity, Immunologic; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocytes - immunology; Humans; Immunology; Infusions, Intravenous; interferon‐dependent; Killer Cells, Natural - immunology; Leukocytes, Mononuclear - immunology; Liver - cytology; Liver - immunology; Liver Neoplasms - immunology; Liver Neoplasms - secondary; Medical research; Medical sciences; NK cells; Oncolytic Virotherapy - methods; Phenotype; Reoviridae - immunology; Reovirus; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Human; Load; NK cells; Rectal disease; Digestive system; Liver; Cytokine; Colorectal cancer; Hepatic disease; Cytotoxicity; colorectal liver metastases; Malignant tumor; interferon-dependent; Colonic disease; Natural killer cell; Blood cell; Cancerology; Mononuclear cell; reovirus; Digestive diseases; Intestinal disease; Interferon; Liver metastasis; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27918

Reovirus is a promising oncolytic virus, acting by both direct and immune‐mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus‐loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus‐treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon‐dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune‐mediated therapy against human colorectal or other cancers metastatic to the liver. What's new? Reovirus can deliver a double whammy to cancer: it hunts down and destroys ras‐activated tumor cells, and it can also fire up the immune system against the tumor. The immune system, however, is a fickle ally; in addition to attacking tumor cells, an efficient immune response also rids the body of reovirus, hindering therapy. This study investigated whether therapeutic reovirus could be shielded from immune assault. They showed that loading reovirus onto blood mononuclear cells provides safe transportation to target cells, in this case, colorectal tumor cells, and the reovirus‐loaded immune cells themselves also launch an attack against tumor cells. Reovirus appears to be a promising new avenue for cancer treatment.