Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity.
UNLABELLED:VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4771163?pdf=render |
| _version_ | 1818162593569701888 |
|---|---|
| author | Gregory N Dietsch Hailing Lu Yi Yang Chihiro Morishima Laura Q Chow Mary L Disis Robert M Hershberg |
| author_facet | Gregory N Dietsch Hailing Lu Yi Yang Chihiro Morishima Laura Q Chow Mary L Disis Robert M Hershberg |
| author_sort | Gregory N Dietsch |
| collection | DOAJ |
| description | UNLABELLED:VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation, increases antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1β and IL-18 from monocytic cells through coordinated actions on both TLR8 and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In vitro, VTX-2337 primed monocytic cells to produce pro-IL-1β, pro-IL-18, and caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the release of mature IL-1β family cytokines. Inhibition of caspase-1 blocked VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on production of other TLR8-induced mediators such as TNFα. IL-18 activated natural killer cells and complemented other stimulatory pathways, including FcγRIII and NKG2D, resulting in IFNγ production and expression of CD107a. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma IL-1β and IL-18 levels in cynomolgus monkeys administered VTX-2337. These results are highly relevant to clinical studies of combination VTX-2337/cetuximab treatment. Cetuximab, a clinically approved, epidermal growth factor receptor-specific monoclonal antibody, activates NK cells through interactions with FcγRIII and facilitates ADCC of tumor cells. Our preliminary findings from a Phase I open-label, dose-escalation, trial that enrolled 13 patients with recurrent or metastatic SCCHN show that patient NK cells become more responsive to stimulation by NKG2D or FcγRIII following VTX-2337 treatment. Together, these results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 can complement FcγRIII engagement and may augment clinical responses in SCCHN patients treated with cetuximab. TRIAL REGISTRATION:ClinicalTrials.gov NCT01334177. |
| first_indexed | 2024-12-11T16:36:08Z |
| format | Article |
| id | doaj.art-76249c953a2e4007813d22b488c7aa4a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T16:36:08Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-76249c953a2e4007813d22b488c7aa4a2022-12-22T00:58:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01112e014876410.1371/journal.pone.0148764Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity.Gregory N DietschHailing LuYi YangChihiro MorishimaLaura Q ChowMary L DisisRobert M HershbergUNLABELLED:VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation, increases antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1β and IL-18 from monocytic cells through coordinated actions on both TLR8 and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In vitro, VTX-2337 primed monocytic cells to produce pro-IL-1β, pro-IL-18, and caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the release of mature IL-1β family cytokines. Inhibition of caspase-1 blocked VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on production of other TLR8-induced mediators such as TNFα. IL-18 activated natural killer cells and complemented other stimulatory pathways, including FcγRIII and NKG2D, resulting in IFNγ production and expression of CD107a. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma IL-1β and IL-18 levels in cynomolgus monkeys administered VTX-2337. These results are highly relevant to clinical studies of combination VTX-2337/cetuximab treatment. Cetuximab, a clinically approved, epidermal growth factor receptor-specific monoclonal antibody, activates NK cells through interactions with FcγRIII and facilitates ADCC of tumor cells. Our preliminary findings from a Phase I open-label, dose-escalation, trial that enrolled 13 patients with recurrent or metastatic SCCHN show that patient NK cells become more responsive to stimulation by NKG2D or FcγRIII following VTX-2337 treatment. Together, these results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 can complement FcγRIII engagement and may augment clinical responses in SCCHN patients treated with cetuximab. TRIAL REGISTRATION:ClinicalTrials.gov NCT01334177.http://europepmc.org/articles/PMC4771163?pdf=render |
| spellingShingle | Gregory N Dietsch Hailing Lu Yi Yang Chihiro Morishima Laura Q Chow Mary L Disis Robert M Hershberg Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PLoS ONE |
| title | Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. |
| title_full | Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. |
| title_fullStr | Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. |
| title_full_unstemmed | Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. |
| title_short | Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. |
| title_sort | coordinated activation of toll like receptor8 tlr8 and nlrp3 by the tlr8 agonist vtx 2337 ignites tumoricidal natural killer cell activity |
| url | http://europepmc.org/articles/PMC4771163?pdf=render |
| work_keys_str_mv | AT gregoryndietsch coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT hailinglu coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT yiyang coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT chihiromorishima coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT lauraqchow coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT maryldisis coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity AT robertmhershberg coordinatedactivationoftolllikereceptor8tlr8andnlrp3bythetlr8agonistvtx2337ignitestumoricidalnaturalkillercellactivity |