Acute and innocuous CpG-C immune stimulation potentiates host resistance to hepatic metastases of colon cancer and protects against immunosuppressive effects of surgery

Abstract

Liver metastases are a major cause of cancer-related mortality. Marginating-hepatic (MH)-NK cells are strategically located in the liver sinusoids to physically interact and lyse circulating tumor cells. In cancer patients, the short peri-operative period is now recognized as critical in determining the progression of remaining malignant disease into established metastases. However, the benefits of immune stimulation have rarely been studied peri-operatively, given the short time frame and contraindications to surgery. To overcome these obstacles, we herein employed a new synthetic TLR-9 agonist, CpG-C, which has minimal adverse effects in rodents and humans. Our results indicated that a single pre-operative CpG-C administration tripled MH-NK cell numbers, and dramatically increased their per-cell NK cytotoxicity against the standard YAC-1 and the syngeneic CT26 colon cancer cell lines. Furthermore, CpG-C treatment protected mice from laparotomy-induced immune suppression, based on examining MH-NK cytotoxicity levels and several molecular markers of NK-cell function, including NKp46, CD49b, CD11b, and NKG2A. Importantly, this short and innocuous CpG-C treatment dramatically reduced the number of hepatic metastases developed 3-weeks following surgical inoculation of CT26 through the hepatic portal vein. These beneficial effects are mediated through activation of NK cells, as NK depletion by anti-asialo GM1 completely abrogated them. Overall, this approach is feasible in cancer patients, and may introduce a new peri-operative intervention to improve long-term cancer outcomes during the critical and unexploited peri-operative time frame.