Interferon gamma-producing ability in blood lymphocytes of patients with lung cancer through activation of the innate immune system by BCG cell wall skeleton

Matsumoto, Misako; Seya, Tsukasa; Kikkawa, Satomi; Tsuji, Shoutaro; Shida, Kyoko; Nomura, Midori; Kurita-Taniguchi, Mitsue; Ohigashi, Hajime; H, Yokouchi; Takami, Hirokazu; Hayashi, Akira; Azuma, Ichiro; Masaoka, T; Kodama, Ken; Toyoshima, Kumao

doi:10.1016/s1567-5769(01)00071-6

Cited by 42 publications

(37 citation statements)

References 33 publications

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“…No liberation of IFN-inducible genes was noticed in either case (data not shown), suggesting no involvement of the TRIF/TICAM-1 pathway (29,31). Because BCG-CWS has been applied in immunotherapy for cancer (46,50), synthetic MDP derivatives with high DC maturation potential may serve as good candidates and clinically useful adjuvants that clear Good Manufacturing Practice criteria and promise high quality of life at low cost. Unfortunately, in previous reports monoacyl MDP could not exert sufficient adjuvancy in a tumorimplanting mouse model (30,48).…”

Section: Discussionmentioning

confidence: 89%

“…It also induces IL-1␤, IL-6, TNF-␣, and GM-CSF (45). These functional profiles of the stearoyl-lysine MDP are reminiscent of the immunoadjuvant properties of BCG-CWS (46). However, it is unlikely that BCG-CWS and stearoyl-lysine MDP derivatives share the activation route in DCs, because stearoyl-lysine MDP does not activate any TLR (45) or adapters (44).…”

Section: Discussionmentioning

confidence: 99%

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Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Uehori

Fukase

Akazawa

et al. 2005

The Journal of Immunology

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6-O-acyl-muramyldipeptides (MDP) with various lengths of fatty acid chains were examined for their dendritic cell (DC) maturation activity expressed through TLRs. Judging from anti-TLR mAb/inhibitor-blocking analysis, MDP derivatives with a single octanoyl or stearoyl fatty acid chain were found to activate TLR2 and TLR4 on human DCs, although intact and diacylated MDP expressed no ability to activate TLRs. Human DC activation profiles by the monoacylated MDP were essentially similar to those by Calmette-Guérin (BCG)-cell wall skeleton (CWS) and BCG-peptidoglycan (PGN) based on their ability to up-regulate costimulators, HLA-DR, β2-microglobulin, and allostimulatory MLR. Monoacylated MDP induced cytokines with similar profiles to BCG-CWS or -PGN, although their potency for induction of TNF-α, IL-12p40, and IL-6 was less than that of BCG-CWS or -PGN. The MDP derivatives initiated similar activation in normal mouse macrophages, but exhibited no effect on TLR2/4-deficient or MyD88-deficient mouse macrophages. Mutation of d-isoGln to l-isoGln in monoacylated MDP did not result in loss of the DC maturation activity, suggesting marginal participation of nucleotide-binding oligomerization domain 2, if any, in monoacyl MDP-dependent DC maturation. These results define the adjuvant activity of 6-O-acyl MDP compounds at the molecular level. They target TLR2/TLR4 and act through the MyD88-dependent pathway in DCs and macrophages. Hence, the unusual combined activation of TLR2 and TLR4 observed with Mycobacterium tuberculosis is in part reflected in the functional properties of monoacylated MDP compounds. These findings infer that the essential minimal requirement for TLR2/4-mediated adjuvancy of BCG lies within a modified MDP.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Uehori

Fukase

Akazawa

et al. 2005

The Journal of Immunology

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“…BCG stimulation of the human innate immune system-as judged by altered levels of interleukin-12 (IL-12), IL-8, IL-10 and IFN-γ in the blood of patients with lung cancer-also demonstrated that BCG has a role in the modulation of the immune system. 19 However BCG is effective predominantly in superficial cancers such as bladder cancer, and similar effects have not been observed in lung 20 cancer or melanoma. 21 Such differential effects may be attributed to cytokine network modulation or functional TLR receptor (Toll like receptors) repertoire expressed by surrounding tissues, recruited cells, or the nature of malignant cells themselves.…”

Section: Adjuvant Cancer Therapy With Bacteriamentioning

confidence: 99%

Microbial based therapy of cancer: A new twist to an age old practice

Punj

Saint‐Dic²,

Daghfal³

et al. 2004

Cancer Biology & Therapy

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The use of bacteria in the regression of tumors has long been known. Various approaches for using bacteria in cancer therapy include the use of bacteria as sensitizing agents for chemotherapy, as delivery agents for cancer drugs and as agents for gene therapy. The tumor regression stimulated by infecting microorganisms has been attributed to activation of the immune system of the host. However, recent studies indicate that when tumorharboring mice with defective immune systems are infected with certain microorganisms, the regression of the tumor is still observed, suggesting that there are other host factors contributing to the microbial associated regression of tumors. Since the use of live or attenuated bacteria for tumor regression has associated toxic effects, studies are in progress to identify a pure microbial metabolite or any component of the microbial cell that might have anti-cancer activity. It has now been demonstrated that a redox protein from Pseudomonas aeruginosa, a cupredoxin, can enter into human cancer cells and trigger the apoptotic cell death. In vivo, this cupredoxin can lead to the regression of tumor growth in immunodeficient mice harboring xenografted melanomas and breast cancer tumors without inducing significant toxic effects, suggesting that it has potential anti-cancer activity. This bacterial protein interacts with p53 and modulates mammalian cellular activity. Hence, it could potentially be used as an anti-cancer agent for solid tumors and has translational value in tumor-targeted or in combinational-biochemotherapy strategies for cancer treatments. Here, we focus on diverse approaches to cancer biotherapy, including bacteriolytic and bacterially-derived anti-cancer agents with an emphasis on their mechanism of action and therapeutic potential.

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“…(14,19,20) and are important for antitumor immunity. (21,22) Interleukin-12 is well known as an antitumor cytokine, (23) and IL-23 shares the IL12p40 subunit with IL-12. …”

mentioning

confidence: 99%

“…(19) Interleukin (IL)-23 and interferon (IFN)-c are the main cytokines induced by BCG-CWS in vivo (14,19,20) and are important for antitumor immunity. (21,22) Interleukin-12 is well known as an antitumor cytokine, (23) and IL-23 shares the IL12p40 subunit with IL-12. (22) Unexpectedly, IL-23 advanced tumor growth in experiments with IL-23R ) ⁄ ) mice or neutralizing antibodies by interacting with Th17 cells.…”

mentioning

confidence: 99%

Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

Akazawa

Inoue²,

Shime

et al. 2010

Cancer Science

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The development of effective immunoadjuvants for tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Gué rin cell wall skeleton (BCG-CWS) in tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating lipopeptide (MALP)-2, which is a Toll-like receptor (TLR)-2 ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) -GNNDESNISFKEK], originally identified in a Mycoplasma species, is a lipopeptide that can be chemically synthesized. A MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an integrin-binding motif and various integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs and splenocytes more efficiently than MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than MALP-2 in inducing migration of DCs to draining lymph node, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named ''adjuvant engineering,'' and the evaluation and improvement of P2C-RGDS constitutes a first step in the development of stronger synthetic adjuvants in the future. (Cancer Sci 2010; 101: 1596-1603 B acterial adjuvants that were used as biological response modifiers (BRM) for cancer immunotherapy in the 1970s have recently been re-evaluated.(1-3) Cancer antigens that had been identified in many laboratories were tested as peptide vaccines for clinical applications, but the peptides alone were not sufficient to fully activate the immune system.(4) These results suggested that the activation of the innate immune system, including dendritic cells (DCs), by a supporting adjuvant was important.(5-8) In peptide vaccine therapy, the T cells of the acquired immune system play an important role in recognizing and attacking tumor cells.(9) Dendritic cells play a key role in the regulation of the acquired immune system by presenting antigen and inducing a primary immune response. The identification of the Toll-like receptor (TLR) family advanced the understanding of DC function and of the role of adjuvants, because almost all microbial adjuvants work as TLR ligands and activate DCs.(10-12) These findings provide the basis for the understanding of the mechanism of adjuvant therapy.Dr Azuma developed BCG-CWS, a cell-wall skeleton preparation of Mycobacterium bovis bacillus Calmette-Guérin, (13,14) as an antitumor immunotherapeutic adjuvant. Although many BRM studies have been discontinued, basic and clinical research on BCG-CWS has...

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Interferon gamma-producing ability in blood lymphocytes of patients with lung cancer through activation of the innate immune system by BCG cell wall skeleton

Cited by 42 publications

References 33 publications

Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Microbial based therapy of cancer: A new twist to an age old practice

Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

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