The TLR7 agonist induces tumor regression both by promoting CD4+T cells proliferation and by reversing T regulatory cell-mediated suppression via dendritic cells

Abstract

Treg-induced immunosuppression is now recognized as a key element in enabling tumors to escape immune-mediated destruction. Although topical TLR7 therapies such as imiquimod have been proved successful in the treatment of dermatological malignancy and a number of conditions beyond the FDA-approved indications, the mechanism behind the effect of TLR7 on effector T cell and Treg cell function in cancer immunosurveillance is still not well understood. Here, we found that Loxoribin, one of the TLR7 ligands, could inhibit tumor growth in xenograft models of colon cancer and lung cancer, and these anti-tumor effects of Loxoribin were mediated by promoting CD4+T cell proliferation and reversing Treg-mediated suppression via dendritic cells (DCs). However, deprivation of IL-6 using a neutralizing antibody abrogated the ability of Loxoribin-treated DCs, which reversed the Treg cell-mediated suppression. Furthermore, adoptive transfer of Loxoribin-treated DCs inhibited the tumor growth in vivo. Thus, this study links TLR7 signaling to the functional control of effector T cells and Treg cells and identifies Loxoribin as a new therapeutic strategy in cancer treatment, which may offer new opportunities to improve the outcome of cancer immunotherapy.

CpG Oligonucleotides as Cancer Vaccine Adjuvants

“…TLR7 agonists have additional effects on immune cells. For example, loxorubin can inhibit tumor growth by promoting CD4 T cell proliferation and modulating the suppressive activity of Tregs [ 121 ].…”

In Ovo Delivered Toll-Like Receptor 7 Ligand, Resiquimod Enhances Host Responses against Infectious Bronchitis Corona Virus (IBV) Infection

“…In the current study, we saw a significant increase in the expansion of CD8α+ T cell population in resiquimod pretreated lungs as compared with PBS pretreated control lungs. Although, the mechanisms underlying the ability of resiquimod to increase CD8α+ T cell recruitment in the absence of antigen stimulation is unclear, evidence of a different TLR7 agonist, promoting proliferation of naïve T cells has been observed in vitro in the presence of antigen presenting cells, dendritic cells (DCs) [26]. In addition to CD8α+ T cell recruitment, macrophage recruitment has also been higher in the lungs following pre-hatch delivery of resiquimod.…”

Enhancement of adoptive T cell transfer with single low dose pretreatment of doxorubicin or paclitaxel in mice

“…Recently, Loxoribin, a TLR7 agonist, has been shown to be able to shrink the tumor through augmenting the proliferation of CD4+ T cells and lowering the frequency of Tregs, which is mediated by elevated IL-6 level secreted by DCs. [ 42 ]. IL-12 has been shown with anti-tumor effect and could enhance expressions of other cytokines involving in both innate and adaptive immunity [ 43 ].…”