Abstract

The agonists of toll-like receptors (TLRs) have been actively pursued for their anti-tumor potentials, either as monotherapy or as adjuvants to vaccination or other therapeutic modalities (1). A search on ClinicalTrials.gov using the key words “TLR” and “cancer” returned 34 listings. The idea of using TLR agonist to provide a “danger signal” and break tolerance to tumor antigens has been well embraced by tumor immunologists. However, the promise of TLR agonists-based immunotherapy remains to be realized in the clinic, and only very few TLR agonists have been approved by the FDA. For example, bacillus Calmette–Guerin (BCG) and imiquimod have been approved as standalone therapies, whereas monophosphoryl lipid A (MPL) was approved as a vaccine component. A review of recently published literature on the use of TLR agonists in cancer setting revealed a common mechanism that might have explained the underperformance of TLR agonists as cancer therapeutics: induction of immune suppressive factors that put a break on the TLR agonists-induced inflammation. As shown in Figure ​Figure1,1, TLR agonists have immune stimulatory effects through the induction of costimulatory molecules (CD80, CD86, and CD40) on dendritic cells (DCs) and inflammatory cytokines (TNF-α and IL-12) that polarize Th1 immune response. On the other hand, TLR agonists have immune inhibitory effects as evidenced by the induction of several immune suppressive factors, including IL-10, T regulatory cells (Treg), and PD-L1, all of which could dampen anti-tumor immunity. The following is a brief summary on TLR agonists-induced self-regulatory feedback and the indication for cancer immunotherapy. Figure 1 Schematic diagram showing that PD-1/PD-L1 blockade may enhance TLR-based immunotherapy by tipping the balance between the immune stimulatory and inhibitory effects of TLR agonists. Treatment with TLR agonists in tumor-bearing host not only induces pro-inflammatory ...

Highlights

  • INDUCTION OF IL-10 IL-10 is an immune suppressive cytokine that inhibits the activity of Th1 cells, impeding viral clearance and anti-tumor Th1 immunity

  • TLR4 signaling with LPS was shown to activate innate IL-10 production in response to Bordetella pertussis, which both directly, and by promoting the induction of IL-10-secreting type 1 regulatory T cells (Tr1), inhibit Th1 responses and limit inflammatory pathology in the lungs during infection with B. pertussis [6]

  • IL-10 induction was observed in a mouse model of implanted TSA breast cancer, where topical imiquimod was shown to synergize with radiation and low-dose cyclophosphamide in inhibiting tumor growth [8]

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Summary

Introduction

INDUCTION OF IL-10 IL-10 is an immune suppressive cytokine that inhibits the activity of Th1 cells, impeding viral clearance and anti-tumor Th1 immunity. In MMTV/neu-transgenic mice, a model of human HER2+ breast cancer, topical treatment with TLR7 agonist imiquimod induced IL-10, and the major source of IL-10 was Tr1 cells [4]. IL-10 induction was observed in a mouse model of implanted TSA breast cancer, where topical imiquimod was shown to synergize with radiation and low-dose cyclophosphamide in inhibiting tumor growth [8].

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