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

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 ( TLR 4) monoclonal antibodies ( mA bs) activate only cell‐surface TLR 4; in contrast, lipopolysaccharide (LPS) activates both TLR 4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti‐ TLR 4 mA b in T‐cell‐mediated antitumour immunity. The anti‐ TLR 4 mA b 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‐ TLR 4 mA b in combination, but not individually. The antitumour effect of anti‐ PD ‐1 mA b was enhanced in mice administered with OVA plus the anti‐ TLR 4 mA b. The OVA‐specific IFN ‐γ‐producing CD 8 T‐cells were induced by administration of OVA and the anti‐ TLR 4 mA b. The suppression of tumour growth was diminished by depletion of CD 8, but not CD 4, T‐cells. The inflammatory response to the anti‐ TLR 4 mA b 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‐ TLR 4 mA b) 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‐ TLR 4 mA b induces potent CD 8 T‐cell‐dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti‐ TLR 4 mA b has potential as an adjuvant for use in vaccines against cancer.