Polysaccharide Krestin Is a Novel TLR2 Agonist that Mediates Inhibition of Tumor Growth via Stimulation of CD8 T Cells and NK Cells

Lu, Hailing; Yang, Yi; Gad, Ekram; Wenner, Cynthia A.; Chang, Amy; Larson, Emily R.; Dang, Yushe; Martzen, Mark R.; Standish, Leanna J.; Disis, Mary L.

doi:10.1158/1078-0432.ccr-10-1763

Cited by 128 publications

(99 citation statements)

References 47 publications

(53 reference statements)

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“…We recently demonstrated that the level of TLR2 expressed on B16F10 melanoma cells determines their invasive activity in response to the endogenous factors released from tumor cells [12] . However, contradictory observations by others indicate that TLR2 activation is able to induce inflammatory cytokines and activate NK cells in vitro and in vivo and protect mice from tumor development and progression [31,32] . In the current study, we find that blocking TLR2 effectively reverses the immunosuppressive characteristics of the microenvironment by suppressing the expression of TGF-β1, IDO, and COX2 and attenuating the infiltration of M2 and Tregs cells.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Yan

Hua²,

Liu³

et al. 2012

Acta Pharmacol Sin

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Aim: To develop a rational immunotherapy against tumor metastasis by combining a Toll-like-receptor 2 (TLR2)-neutralizing antibody with a TLR9 agonist CpG ODN, and then investigate the mechanism of action for this combinational regimen. Methods: After mouse melanoma B16-F10 cell inoculation, female C57BL/6 mice were treated with either CpG ODN (0.5 mg/kg) or the anti-TLR2 antibody (200 μg/kg), or with a combination of the two agents. Pulmonary metastases were evaluated by counting metastatic nodes on the lung surface using anatomical microscopy. Flow cytometry was used to evaluate the cytotoxicity of the immune cells in tumor-draining lymph nodes, the cell population in the spleen, and the infiltration of immune cells within the lungs. Cytokine and enzyme expression in the lung tissue was evaluated using ELISA or immunostaining. Results: Anti-metastatic effects were detected in mice treated with either CpG ODN or the anti-TLR2 antibody alone. However, treatment with CpG ODN plus the anti-TLR2 antibody synergistically suppressed the metastasis as compared with treatment with either single agent. The combinational treatment resulted in enhanced infiltration of natural killer cells and cytotoxic T cells, reduced recruitment of type 2 macrophages and Tregs, and decreased expression of immunosuppressive factors including TGF-β1, cyclooxygenase-2 and indoleamine 2,3-dioxygenase, thus stimulated tumor cytotoxicity and suppressed metastasis. The anti-metastatic effect of the combinational regimen was further confirmed in spontaneous metastatic mouse model of Lewis lung carcinoma. Conclusion: Our studies suggest that combining a TLR9 agonist with an anti-TLR2 antibody, which eliminates immunosuppressive factors from the tumor environment, is critical for an effective anti-metastatic immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Yan

Hua²,

Liu³

et al. 2012

Acta Pharmacol Sin

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“…The activity of specific TLR agonists was assessed using the secretory embryonic alkaline phosphatase (SEAP) reporter gene that is linked to NF-kB activation in response to TLR stimulation. Measurement of SEAP activity using the Quanti-blue substrate (InvivoGen) after TLR agonist treatment was carried out similarly as described previously (24).…”

Section: Nf-kb Activation In Hek Cells Transfected With Tlrsmentioning

confidence: 99%

VTX-2337 Is a Novel TLR8 Agonist That Activates NK Cells and Augments ADCC

Dietsch

Matthews

et al. 2012

Clinical Cancer Research

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154

148

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Purpose: We aim to characterize VTX-2337, a novel Toll-like receptor (TLR) 8 agonist in clinical development, and investigate its potential to improve monoclonal antibody-based immunotherapy that includes the activation of natural killer (NK) cells.Experimental Design: HEK-TLR transfectants were used to compare the selectivity and potency of VTX-2337, imiquimod, CpG ODN2006, and CL075. The ability of VTX-2337 to induce cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC) and activation of specific immune cell subsets was examined. The potential for VTX-2337 to activate NK cell activity through direct and indirect mechanisms was also investigated. Finally, we tested the potential for VTX-2337 to augment antibodydependent cell-mediated cytotoxicity (ADCC), especially in individuals with low-affinity FcgR3A singlenucleotide polymorphism (SNP).Results: VTX-2337 selectively activates TLR8 with an EC 50 of about 100 nmol/L and stimulates production of TNFa and interleukin (IL)-12 from monocytes and myeloid dendritic cells (mDC). VTX-2337 stimulates IFNg production from NK cells and increases the cytotoxicity of NK cells against K562 and ADCC by rituximab and trastuzumab. Effects of VTX-2337 on NK cells were, in part, from direct activation as increased IFNg production and cytotoxic activity were seen with purified NK cells. Finally, VTX-2337 augments ADCC by rituximab in PBMCs with different FcgR3A genotypes (V

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“…PSK has been reported to activate various immunologically-competent cells 35) -38) . NK cells are also thought to exhibit anti-tumor effects when activated by PSK 36)39) 40) . In this study, the NK cell population was significantly higher in the PSK (＋) group compared with the PSK(−) group.…”

Section: Figure─3mentioning

confidence: 99%

Analysis of the Effects of Alleviating Adverse Events and Improving Completion in Colorectal Cancer Patients with Postoperative Adjuvant Chemotherapy with PSK

Sugimoto

Takahashi

Ishiyama

et al. 2012

Juntendo Medical Journal

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Objective：It is well known that anti-cancer drugs generate reactive oxygen species and lipoperoxides in cancer patients, and that these free radicals can give rise to adverse events. It has been reported that free radical effects might be attenuated by antioxidants. Recent reports have indicated that Protein-bound polysaccharide K(PSK) exhibits antioxidant effects in addition to its anti-tumor effects. However, there have been few reports investigating whether the antioxidant effects induced by PSK can actually alleviate the adverse events of anti-cancer drugs. In an attempt to alleviate the adverse events and improve completion of oral anti-cancer drugs, we performed a randomized, controlled trial of oral UFT／LV plus PSK as postoperative adjuvant chemotherapy for stage II and III colorectal cancer.Materials：Fifty patients who had undergone curative resection of high-risk stage II or stage III adenocarcinoma of the colon and rectum between May 2008 and May 2010 were enrolled in this study.Methods：Patients were randomly assigned to the UFT／LV treatment (PSK (−) ) and the UFT／LV plus PSK treatment (PSK (＋) ) groups at a 1：1 ratio. The PSK (−) group received UFT (300 mg／m 2 ／day) and LV (75 mg／day) , starting 4─8 weeks after surgery and continuing for 6 months or until the diagnosis of tumor recurrence. The PSK(＋) group received PSK(3. 0g／ day) every day in addition to the UFT／LV treatment. Patient backgrounds, adverse events, completion of oral administration, laboratory test, stress indices, such as Reactive Oxygen Metabolites Test(d─ROMs Test) and salivary chromogranin A, and NK cell population were analyzed.Results：Nine patients(36. 0％) and 11 patients(44. 0％) had overall adverse events in the PSK(−) and PSK(＋) groups, respectively. There was no significant difference in the incidence of adverse events between the PSK(−) and PSK(＋) groups.Twenty-two patients(88. 0％) and 23 patients(92. 0％) completed oral administration of anti-cancer drugs in the PSK(−) and PSK(＋) groups, respectively. There was no significant difference in completion of oral administration between the two groups. In laboratory tests, no significant differences were observed between the two groups. There was no significant difference in the d─ROMs Test between the two groups. Similarly, no significant difference was observed in the salivary chromogranin A. The NK cell population in the PSK (＋) group was significantly higher than that in the PSK (−) group (p ＝ 0. 03) .Conclusions：There were no significant differences in the incidence of adverse events between the PSK(−) and PSK(＋)groups. In addition, completion of oral administration was high in both groups, and therefore no effects of PSK to alleviate adverse events and improve completion of oral administration of anti-cancer drugs were recognized. In the future, it will be necessary to investigate whether or not PSK can reduce adverse events and improve the completion of oral administration of anticancer drugs when PSK is combined with other regimens with a higher incidence of adverse events o...

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Polysaccharide Krestin Is a Novel TLR2 Agonist that Mediates Inhibition of Tumor Growth via Stimulation of CD8 T Cells and NK Cells

Cited by 128 publications

References 47 publications

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

VTX-2337 Is a Novel TLR8 Agonist That Activates NK Cells and Augments ADCC

Analysis of the Effects of Alleviating Adverse Events and Improving Completion in Colorectal Cancer Patients with Postoperative Adjuvant Chemotherapy with PSK

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