Prevention of liver metastases through perioperative acute CpG-C immune stimulation

Liat Sorski, Rivka Melamed, Ben Levi, Pini Matzner, Hagar Lavon, Ella Rosenne, Lee Shaashua, Itay Ricon, Elad Sandbank, Amit Benbenishty, Shamgar Ben-Eliyahu

Research output: Contribution to journalArticlepeer-review


Following excision of colorectal tumors, metastatic disease is prevalent, primarily occurs in the liver, and is highly predictive of poor prognosis. The perioperative period is now recognized as critical in determining the incidence of postoperative metastases and long-term cancer outcomes. Thus, various perioperative prophylactic interventions are currently studied during this time frame. However, immune stimulation during the perioperative period has rarely been attempted due to specific contraindications to surgery and various adverse effects. Here, to prevent liver metastases, we perioperatively employed a TLR-9 agonist, CpG-C, which exhibits minimal pyrogenic and other adverse effects in patients. We found that marginating-hepatic (MH) cells in BALB/c mice contained high percentage of NK cells, but exhibited negligible NK cytotoxicity, as previously reported in humans. However, a single CpG-C administration (25-100 µg/mouse) doubled MH-NK cell numbers, increased NK cell activation and maturation markers (NKp46, CD11b), decreased the inhibitory NKG2A ligand, and dramatically increased MH-NK-cell cytotoxicity against the syngeneic CT26 colon cancer line. Moreover, in operated mice, this innocuous intervention also markedly improved resistance to CT26 and MC38 hepatic metastases in BALB/c and C57BL/6 mice, respectively. Beneficial effects of CpG-C were mediated through activation of MH-NK cells, as indicated by an in vivo NK depletion study. Last, CpG-C protected against surgery-induced suppression of MH-NK cytotoxicity and improved their activation indices. Thus, we suggest that systemic perioperative CpG-C treatment should be considered and studied as a novel therapeutic approach to improve long-term cancer outcomes in colorectal cancer patients.

Original languageEnglish
Pages (from-to)2021-2031
Number of pages11
JournalCancer Immunology, Immunotherapy
Issue number10
StatePublished - 1 Oct 2020


  • Colorectal cancer
  • CpG-C
  • Immunotherapy
  • Liver metastasis
  • Marginating hepatic NK cells
  • Perioperative period

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research


Dive into the research topics of 'Prevention of liver metastases through perioperative acute CpG-C immune stimulation'. Together they form a unique fingerprint.

Cite this