Adjuvant for vaccine immunotherapy of cancer – focusing on Toll‐like receptor 2 and 3 agonists for safely enhancing antitumor immunity

<jats:p>Immune‐enhancing adjuvants usually targets antigen (Ag)‐presenting cells to tune up cellular and humoral immunity. <jats:styled-content style="fixed-case">CD</jats:styled-content>141<jats:sup>+</jats:sup> dendritic cells (<jats:styled-content style="fixed-case">DC</jats:styled-content>) represent the professional Ag‐presenting cells in humans. In response to microbial pattern molecules, these <jats:styled-content style="fixed-case">DC</jats:styled-content>s upgrade the maturation stage sufficient to improve cross‐presentation of exogenous Ag, and upregulation of <jats:styled-content style="fixed-case">MHC</jats:styled-content> and costimulators, allowing <jats:styled-content style="fixed-case">CD</jats:styled-content>4/<jats:styled-content style="fixed-case">CD</jats:styled-content>8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These <jats:styled-content style="fixed-case">DC</jats:styled-content>s also facilitate natural killer‐mediated cell damage. Toll‐like receptors (<jats:styled-content style="fixed-case">TLR</jats:styled-content>s) and their signaling pathways in <jats:styled-content style="fixed-case">DC</jats:styled-content>s play a pivotal role in <jats:styled-content style="fixed-case">DC</jats:styled-content> maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse <jats:styled-content style="fixed-case">CD</jats:styled-content>8α<jats:sup>+</jats:sup> <jats:styled-content style="fixed-case">DC</jats:styled-content>s express <jats:styled-content style="fixed-case">TLR</jats:styled-content>7 and <jats:styled-content style="fixed-case">TLR</jats:styled-content>9 in addition to the <jats:styled-content style="fixed-case">TLR</jats:styled-content>2 family (<jats:styled-content style="fixed-case">TLR</jats:styled-content>1, 2, and 6) and <jats:styled-content style="fixed-case">TLR</jats:styled-content>3, whereas human <jats:styled-content style="fixed-case">CD</jats:styled-content>141<jats:sup>+</jats:sup> <jats:styled-content style="fixed-case">DC</jats:styled-content>s exclusively express the <jats:styled-content style="fixed-case">TLR</jats:styled-content>2 family and <jats:styled-content style="fixed-case">TLR</jats:styled-content>3. Although human and mouse plasmacytoid <jats:styled-content style="fixed-case">DC</jats:styled-content>s commonly express <jats:styled-content style="fixed-case">TLR</jats:styled-content>7/9 to respond to their agonists, the results on mouse adjuvant studies using <jats:styled-content style="fixed-case">TLR</jats:styled-content>7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, <jats:styled-content style="fixed-case">TLR</jats:styled-content>2 and <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 are similarly expressed in both human and mouse Ag‐presenting <jats:styled-content style="fixed-case">DC</jats:styled-content>s. Bacillus Calmette–Guerin peptidoglycan and polyinosinic–polycytidylic acid are representative agonists for <jats:styled-content style="fixed-case">TLR</jats:styled-content>2 and <jats:styled-content style="fixed-case">TLR</jats:styled-content>3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant <jats:styled-content style="fixed-case">TLR</jats:styled-content>s. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of <jats:styled-content style="fixed-case">TLR</jats:styled-content>2 and <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 agonists in vaccine‐adjuvant immunotherapy for cancer.</jats:p>