Combination therapy with TLR7 agonist and radiation is effective for the treatment of solid cancer

Toll like receptors (TLRs) are well-conserved pattern recognition receptors required for sensing pathogenic elements such as bacterial lipopolysaccharides, DNA, or viral RNA. TLR1, TLR2, TLR4, TLR5, and TLR6 are present on the surface of cells and recognize bacterial and fungal components. In contrast, TLR3, TLR7, and TLR9 function intracellularly by recognizing of the nucleic acids (DNA or RNA) of pathogens. The host innate immune responses are enhanced through the recognition of pathogen-associated molecules by these TLRs. Moreover, the activation of innate immunity by TLR agonists effectively drives adaptive immunity via the production of several cytokines [e.g., interleukin (IL)-12b] and the activation of antigen-presenting cells (APCs). IL-12b is a pivotal cytokine for the induction of Th1 immune response and antigen-specific cytotoxic T cells (CTLs) (1). These inductions are extremely important for cellular immune response in the host and may lead to elimination of viruses or establishment of several cancer therapies. The expression of costimulatory molecules (CD40, CD80 and CD86) on APCs is enhanced after stimulation by several TLR agonists (2,3). These costimulatory molecules are intricately involved in the induction of acquired and antigen-specific immune responses. Therefore, TLR agonists can induce cellular immune response in viral infection and cancer and have the potential to treat cancer. Indeed, the anti-tumor effects of several TLR agonists were recently evaluated in basic studies and clinical trials (4,5). In particular, one TLR7 agonist, imiquimod (Aldara 5% cream, 3M), has been approved for clinical use by the FDA. This agent is topically used for the treatment of basal cell carcinoma and other skin tumors. However, many investigators have confirmed that monotherapy by some TLR agonists was not sufficient to completely eliminate the tumor in animal studies and clinical trials. Therefore, combination therapy with TLR agonists and other anti-cancer treatment is being evaluated. Traditional treatments for patients with cancer are surgery, chemotherapy, and radiation. Although these traditional treatments are effective for early stages of cancer, they have a limited role in advanced cancer. Recently, cancer immunotherapy has received attention as a new strategy of cancer therapy. Several studies have evaluated the anti-cancer effects of the combination of TLRs agonists and traditional cancer therapy (6).