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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 10/2020

01-10-2020 | Metastasis | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 10/2020

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Abstract

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.
Literature
1.
2.
Morris EJ et al (2010) Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 97(7):1110–1118PubMed
3.
Neeman E, Zmora O, Ben-Eliyahu S (2012) A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res 18(18):4895–4902PubMedPubMedCentral
4.
Horowitz M et al (2015) Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol 12(4):213–226PubMedPubMedCentral
5.
Yamaguchi K et al (2000) Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg 232(1):58–65PubMedPubMedCentral
6.
Ben-Eliyahu S (2003) The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology. Brain Behav Immun 17(Suppl 1):S27–S36PubMed
7.
Fisher B et al (1989) Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49(8):1996–2001PubMed
8.
Shaashua L et al (2017) Perioperative COX-2 and beta-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin Cancer Res 23(16):4651–4661PubMedPubMedCentral
9.
Melamed R et al (2005) Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav Immun 19(2):114–126PubMed
10.
Wisse E et al (1976) The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res 173(4):423–435PubMed
11.
Kaneda K, Wake K (1983) Distribution and morphological characteristics of the pit cells in the liver of the rat. Cell Tissue Res 233(3):485–505PubMed
12.
13.
Carson WE et al (1999) A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells. J Immunol 162(8):4943–4951PubMed
14.
Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760PubMed
15.
Sivori S et al (2006) Comparison of different CpG oligodeoxynucleotide classes for their capability to stimulate human NK cells. Eur J Immunol 36(4):961–967PubMed
16.
Poeck H et al (2004) Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 103(8):3058–3064PubMed
17.
Kwong B, Liu H, Irvine DJ (2011) Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials 32(22):5134–5147PubMedPubMedCentral
18.
Guiducci C et al (2006) Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med 203(8):1999–2008PubMedPubMedCentral
19.
Liu M et al (2019) Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don’t-eat-me’ signal. Nat Immunol 20(3):265–275PubMedPubMedCentral
20.
Corbett TH et al (1975) Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35(9):2434–2439PubMed
21.
Sorski L et al (2014) The impact of surgical extent and sex on the hepatic metastasis of colon cancer. Surg Today 44(10):1925–1934PubMed
22.
Sorski L et al. (2016) Selective harvesting of marginating-hepatic leukocytes. J Vis Exp, 113
23.
Melamed R et al (2010) The marginating-pulmonary immune compartment in rats: characteristics of continuous inflammation and activated NK cells. J Immunother 33(1):16–29PubMedPubMedCentral
24.
Vollmar B, Menger MD (2009) The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 89(4):1269–1339PubMed
25.
Zhang J et al (2005) Isolation of lymphocytes and their innate immune characterizations from liver, intestine, lung and uterus. Cell Mol Immunol 2(4):271–280PubMed
26.
Agorku DJ et al (2019) CD49b, CD87, and CD95 are markers for activated cancer-associated fibroblasts whereas CD39 marks quiescent normal fibroblasts in murine tumor models. Front Oncol 9:716PubMedPubMedCentral
27.
Hemmi H et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408(6813):740–745PubMed
28.
Takeshita F et al (2001) Cutting edge: role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 167(7):3555–3558PubMed
29.
Ashkar AA, Rosenthal KL (2002) Toll-like receptor 9, CpG DNA and innate immunity. Curr Mol Med 2(6):545–556PubMed
30.
Krieg AM et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374(6522):546–549PubMed
31.
Krug A et al (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol 31(7):2154–2163PubMed
32.
Della Chiesa M et al (2006) Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses. Blood 108(12):3851–3858PubMed
33.
Mathan TS, Figdor CG, Buschow SI (2013) Human plasmacytoid dendritic cells: from molecules to intercellular communication network. Front Immunol 4:372PubMedPubMedCentral
34.
Adams DH, Eksteen B, Curbishley SM (2008) Immunology of the gut and liver: a love/hate relationship. Gut 57(6):838–848PubMed
35.
Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3(1):51–62PubMed
36.
Lassen MG et al (2010) Intrahepatic IL-10 maintains NKG2A + Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol 184(5):2693–2701PubMedPubMedCentral
37.
38.
Jinushi M et al (2007) Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology 120(1):73–82PubMedPubMedCentral
39.
Nishikado H et al (2011) NK cell-depleting anti-asialo GM1 antibody exhibits a lethal off-target effect on basophils in vivo. J Immunol 186(10):5766–5771PubMed
40.
Victorino F et al (2015) Tissue-resident NK cells mediate ischemic kidney injury and are not depleted by anti-asialo-GM1 antibody. J Immunol 195(10):4973–4985PubMedPubMedCentral
41.
Benish M et al (2008) Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol 15(7):2042–2052PubMed
42.
Glasner A et al (2010) Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184(5):2449–2457PubMed
43.
Clinthorne JF et al (2013) NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol 190(2):712–722PubMed
44.
Goldfarb Y et al (2009) CpG-C oligodeoxynucleotides limit the deleterious effects of beta-adrenoceptor stimulation on NK cytotoxicity and metastatic dissemination. J Immunother 32(3):280–291PubMedPubMedCentral
45.
Metadata
Title
Prevention of liver metastases through perioperative acute CpG-C immune stimulation
Authors
Liat Sorski
Rivka Melamed
Ben Levi
Pini Matzner
Hagar Lavon
Ella Rosenne
Lee Shaashua
Itay Ricon
Elad Sandbank
Amit Benbenishty
Shamgar Ben-Eliyahu
Publication date
01-10-2020
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 10/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-020-02596-7

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