TLR2 Agonist PSK Activates Human NK Cells and Enhances the Antitumor Effect of HER2-Targeted Monoclonal Antibody Therapy

Abstract

Purpose The therapeutic effect of trastuzumab monoclonal antibody (mAb) therapy has been shown to be partially dependent on functional NK cells. Novel agents that enhance NK cell function could potentially improve the anti-tumor effect of trastuzumab. We recently identified polysaccharide krestin (PSK), a natural product extracted from medicinal mushroom Trametes Versicolor, as a potent TLR2 agonist. The current study was undertaken to evaluate the effect of PSK on human NK cells and the potential of using PSK to enhance HER2-targeted mAb therapy. Experimental Design Human PBMC were stimulated with PSK to evaluate the effect of PSK on NK cell activation, IFN-γ production, cytotoxicity, and trastuzumab-mediated ADCC. Whether the effect of PSK on NK cells is direct or indirect was also investigated. Then in vivo experiment in neu transgenic mice was carried out to determine the potential of using PSK to augment the anti-tumor effect of HER2-targeted mAb therapy. Results PSK activated human NK cells to produce IFN-γ and to lyse K562 target cells. PSK also enhanced trastuzumab-mediated ADCC against SKBR3 and MDA-MB-231 breast cancer cells. Both direct and IL-12-dependent indirect effects seem to be involved in the effect of PSK on NK cells. Oral administration of PSK significantly potentiated the anti-tumor effect of anti-HER2/neu mAb therapy in neu-transgenic mice. Conclusion These results demonstrated that PSK activates human NK cells and potentiates trastuzumab-mediated ADCC. Concurrent treatment of PSK and trastuzumab may be a novel way to augment the anti-tumor effect of trastuzumab.

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

“…In this regard, TLR2 agonist treatment was proposed as adjuvant in cancer immunotherapy, 61 because it caused strong activation of NK cells in the context of ADCC induced by the therapeutic antibody Trastuzumab. 50 Our results are in line with recent evidence that exosome release in tumor cells was augmented in response to different drugs, including etoposide, 32 cisplatin and 5-fluorouracil. 43 In summary, our findings add new information on the immunomodulatory action of MM-derived exosomes during the course of chemotherapeutic interventions.…”

“…In line with these results, it was previously shown that IFNg production in response to PSK2, one of the known TLR2 agonists, was mainly associated to the NK CD56 high subset. 50 Thus, it is likely that the higher responsiveness of the CD56 high cell subset to exosome treatment mainly relies on its intrinsic ability to produce cytokines.…”

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

“…PBMCs or purified NK cells were prepared as previously described, and the purity of NK cells was approximately 99% (26). NK cell-mediated cytotoxicity was assessed by Calcein AM release from labeled target cells (26).…”

Critical role of Toll-like receptor signaling in NK cell activation

“…TLR2 agonist polysaccharide krestin (PSK) was also reported to activate human NK cells directly and indirectly with the help of IL-12. Notably, it can enhance the antitumor effect of HER2-targeted monoclonal antibody therapy [71]. In addition, a bacterial fimbrial protein FimH, a novel TLR4 ligand, was recently reported to directly activate human and murine natural killer cells via TLR4-MyD88 pathways [72].…”