An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy. Issue 2 (12th September 2019)

• Record Type: Journal Article
• Authors: Tsukamoto, Hiroki; Kubota, Kanae; Shichiku, Ayumi; Maekawa, Masamitsu; Mano, Nariyasu; Yagita, Hideo; Ohta, Shoichiro; Tomioka, Yoshihisa
• Is Part Of: Immunology. Volume 158:Issue 2(2019)
• Page Start: 136
• Page End: 149
• Publication Date: 2019-09-12
• Subjects: antibodies -- immunotherapy -- inflammasome -- Toll‐like receptors -- tumour immunology; Immunology -- Periodicals
• DOI: 10.1111/imm.13095
• Languages: English
• ISSNs: 0019-2805

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. Abstract : Agonistic anti–TLR4 antibodies activate only cell‑surface TLR4; in contrast, lipopolysaccharide activates both TLR4 and intracellular inflammatory caspases. In this study, we showed that an agonistic anti‐TLR4 antibody induces more potent CD8 T‑cell–dependent antitumor immunity, and an inflammatory reaction of lesser magnitude, than does lipopolysaccharide. The antitumor effect of anti‐PD‐1 antibody was enhanced in combination with the anti‐TLR4 antibody. The agonistic anti‐TLR4 antibody ha s potential as an adjuvant for cancer immunotherapy.