The application of the phagocytic receptor agonists in cancer immunotherapy was studied. Agonists (laminarin, molecules with terminal mannose, N-Formyl-methioninyl-leucyl-phenylalanine) were firmly anchored to the tumor cell surface. When particular agonists of phagocytic receptors were used together with LPS (Toll-like receptor agonist), high synergy causing tumour shrinkage and a temporary or permanent disappearance was observed. Methods of anchoring phagocytic receptor agonists (charge interactions, anchoring based on hydrophobic chains, covalent bonds) and various regimes of phagocytic agonist/LPS mixture applications were tested to achieve maximum therapeutic effect. Combinations of mannan/LPS and f-MLF/LPS (hydrophobic anchors) in appropriate (pulse) regimes resulted in an 80% and 60% recovery for mice, respectively. We propose that substantial synergy between agonists of phagocytic and Toll-like receptors (TLR) is based on two events. The TLR ligand induces early and massive inflammatory infiltration of tumors. The effect of this cell infiltrate is directed towards tumor cells, bearing agonists of phagocytic receptors on their surface. The result of these processes was effective killing of tumor cells. This novel approach represents exploitation of innate immunity mechanisms for treating cancer.

Department of Medical Biology Faculty of Science University of South Bohemia České Budějovice Czech Republic

Department of Pathology Regional Hospital České Budějovice Czech Republic

Department of Virology Veterinary Research Institute Brno Czech Republic

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Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3: 991–998. PubMed

de Vries TJ, Fourkour A, Wobbes T, Verkroost G, Ruiter DJ, et al. (1997) Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions. Cancer Res 57: 3223–3229. PubMed

Algarra I, Collado A, Garrido F (1997) Altered MHC class I antigens in tumors. Int J Clin Lab Res 27: 95–102. PubMed

Jäger E, Ringhoffer M, Karbach J, Arand M, Oesch F, et al. (1996) Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T-cell responses: evidence for immunoselection of antigen-loss variants in vivo. Int J Cancer 66: 470–476. PubMed

Tripathi P, Agrawal S (2006) Non-classical HLA-G antigen and its role in the cancer progression. Cancer Invest 24: 178–186. PubMed

Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437: 141–146. PubMed

Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13: 5262–5270. PubMed

Hamaï A, Benlalam H, Meslin F, Hasmim M, Carré T, et al. (2010) Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune? Tissue Antigens 75: 1–8. PubMed

Langers I, Renoux VM, Thiry M, Delvenne P, Jacobs N (2012) Natural killer cells: role in local tumor growth and metastasis. Biologics 6: 73–82. PubMed PMC

Hayakawa Y, Smyth MJ (2006) Innate immune recognition and suppression of tumors. Adv Cancer Res 95: 293–322. PubMed

Cui Z, Willingham MC, Hicks AM, Alexander-Miller MA, Howard TD, et al. (2003) Spontaneous regression of advanced cancer: Identification of a unique genetically determined, age-dependent trait in mice. PNAS 100: 6682–6687. PubMed PMC

Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, et al. (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. PNAS 103: 7753–7758. PubMed PMC

Jinushi M (2012) The role of innate immune signals in antitumor immunity. Oncoimmunology 1: 189–194. PubMed PMC

Adams S (2009) Toll-like receptor agonists in cancer therapy. Immunotherapy 1: 949–964. PubMed PMC

Kanzler H, Barrat FJ, Hessel EM, Coffman RL (2007) Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 13: 552–559. PubMed

Torosantucci A, Bromuro C, Chiani P, De Bernardis F, Berti F, et al. (2005) A novel glyco-conjugate valine against fungal pathogens. JEM 202: 597–606. PubMed PMC

Kato K, Itoh C, Yasukouchi T, Nagamune T (2004) Rapid protein anchoring into the membranes of mammalian cells using oleyl chain and poly(etylene glycol) derivatives. Biotechnol Prog 20: 897–904. PubMed

Christiaansen JF, Gallardo D, Burnside SS, Nelson AA, Sears DW (1984) Rapid covalent coupling of proteins to cell surfaces: Immunological characterization of viable protein-cell conjugates. J Immunol Methods 74: 229–239. PubMed

Li J, Piao YF, Jiang Z, Chen L, Sun HB (2009) Silencing of signal transducer and activator of transcription 3 expression by RNA interference suppresses growth of human hepatocellular carcinoma in tumor-bearing nude mice. World J Gastroenterol 15: 2602–2608. PubMed PMC

Blanks MJ, Stehle JR, Du W, Adams JM, Willingham MC, et al. (2011) Novel innate cancer killing activity in humans. Cancer Cell Int 11: 26. PubMed PMC

Kingeter LM, Lin X (2012) C-type lectin receptor-induced NF-κB activation in innate immune and infammatory responses. Cell Mol Immunol 9: 105–112. PubMed PMC

Chicoine MR, Won EK, Zahner MC, Parsa AT, Bruce JN, et al. (2001) Intratumoral injection of lipopolysaccharide causes regression of subcutaneously implanted mouse glioblastoma multiforme. Neurosurgery 48: 607–615. PubMed

Mariani CL, Rajon D, Bova FJ, Streit WJ (2007) Nonspecific immunotherapy with intratumoral lipopolysaccharide and zymosan A but not GM-CSF leads to an effective anti-tumor response in subcutaneous RG-2 gliomas. J Neurooncol 85: 231–240. PubMed

Rhee SH, Im E, Pothoulakis C (2008) Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology 135: 518–528. PubMed PMC

Guha M (2012) Anticancer TLR agonists on the ropes. Nature Reviews/Drug Discovery 11: 503–505. PubMed

Kerrigan AM, Brown GD (2009) C-type lectins and phagocytosis. Immunobiology 214: 562–575. PubMed PMC

Le Y, Yang Y, Cui Y, Yazawa H, Gong W, Qiu C, Wang JM (2002) Receptors for chemotactic formyl peptides as pharmacological targets. Int Immunopharmacol 2: 1–13. PubMed

Underhill DM, Gantner B (2004) Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect 6: 1368–1373. PubMed

Vetvicka V (2011) Glucan-immunostimulant, adjuvant, potential drug. World J Clin Oncol 2: 115–119. PubMed PMC

Chan GC, Chan WK, Sze DM (2009) The effects of β-glucan on human immune and cancer cells. J Hematol Oncol 2: 25–36. PubMed PMC

Tsoni SV, Brown GD (2008) β-glucans and Dectin-1. Annals of the New York Academy of Science. 1143: 45–60. PubMed

Frasnelli ME, Tarussio D, Chobaz-Péclat V, Busso N, So A (2005) TLR2 modulates inflammation in zymosan-induced arthritis in mice. Arthritis Res Ther 7: 370–379. PubMed PMC

Willment JA, Lin HH, Reid DM, Taylor PR, Williams DL, et al. (2003) Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide. J Immunol 171: 4569–4573. PubMed

Napper C, Dyson MH, Taylor ME (2001) An extended conformation of the macrophage mannose receptor. J Biol Chem 276: 14759–14766. PubMed

Shepherd VL, Abdolrasulnia R, Garrett M, Cowan HB (1990) Down-regulation of mannose receptor activity in macrophages after treatment with lipopolysaccharide and phorbol esters. J Immunol 145: 1530–1536. PubMed

Dufton N, Perretti M (2010) Therapeutic anti-inflammatory potential of formyl – peptide receptor agonists. Pharmacol Ther 127: 175–188. PubMed

Mandal P, Novotny M, Hamilton TA (2005) Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms. J Immunol 175: 6085–6091. PubMed

Warren TS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, et al. (2010) Resilience to bacterial infection: difference between species could be due to proteins in serum. J Infect Dis 201: 223–232. PubMed PMC

Marquez M, Nilsson S, Lennartsson L, Liu Z, Tammela T, et al. (2004) Charge-dependent targeting: Results in six tumor cell lines. Anticancer Res 24: 1347–1352. PubMed

Riedl S, Rinner B, Asslaber M, Schaider H, Walzer S, et al. (2011) In search of novel target – Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim Biophys Acta 1808: 2638–2645. PubMed PMC

Goodridge HS, Underhill DM, Touret N (2012) Mechanisms of Fc receptor and Dectin-1 activation for phagocytosis. Traffic 13: 1062–107. PubMed

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