An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy

Abstract

Summary Immune‐checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti‐Toll‐like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell‐surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti‐TLR4 mAb in T‐cell‐mediated antitumour immunity. The anti‐TLR4 mAb induced the activation of antigen‐specific T‐cells in adoptive transfer studies. The growth of ovalbumin (OVA)‐expressing tumours was significantly suppressed by administration of OVA and the anti‐TLR4 mAb in combination, but not individually. The antitumour effect of anti‐PD‐1 mAb was enhanced in mice administered with OVA plus the anti‐TLR4 mAb. The OVA‐specific IFN‐γ‐producing CD8 T‐cells were induced by administration of OVA and the anti‐TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T‐cells. The inflammatory response to the anti‐TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF‐κB activation and production of TNF‐α, IL‐6 and IL‐1β. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti‐TLR4 mAb) plus OVA induced no or less‐marked activation of OVA‐specific T‐cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti‐TLR4 mAb induces potent CD8 T‐cell‐dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti‐TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.

Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer

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Tumor cell intrinsic Toll‐like receptor 4 signaling promotes melanoma progression and metastatic dissemination

“…Apart from tumor cell intrinsic roles of TLR4, its activation has also been shown to mediate antitumorigenic properties through microenvironmental effects. Agonistic antibodies against TLR4 have been shown to enhance the effect of an immune checkpoint blockade with anti PD1 antibodies 32 . In experiments with the chemotherapeutic agent paclitaxel, it has been shown that the therapeutic efficacy was dependent on the expression of TLR4 on macrophages 33 .…”

TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer

“…It is urgent to find effective adjuvant treatments to improve the efficacy of immune checkpoint inhibitors. Tumors with low numbers of tumorinfiltrating T cells tend to respond poorly to immune checkpoint blockade therapy (Tsukamoto et al, 2019). As mentioned earlier, TLRs play an important role in immune response.…”

“…Therapy using ARNAX/TAA can overcome anti-PD-L1 resistance (Takeda et al, 2017). OVA/TLR4 mAb can enhance the anti-tumor effect of anti-PD-1 mAb by activating OVA-specific CD8+ T-cells (Tsukamoto et al, 2019). CIRP is a TLR4 ligand.…”