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An agonistic anti‐Toll‐like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy
Author(s) -
Tsukamoto Hiroki,
Kubota Kanae,
Shichiku Ayumi,
Maekawa Masamitsu,
Mano Nariyasu,
Yagita Hideo,
Ohta Shoichiro,
Tomioka Yoshihisa
Publication year - 2019
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.13095
Subject(s) - agonistic behaviour , adjuvant , monoclonal antibody , immunotherapy , medicine , cancer immunotherapy , cancer , immunology , cancer research , antibody , oncology , psychiatry , aggression
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.