Recent advances in the role of toll-like receptors and TLR agonists in immunotherapy for human glioma

Abstract

Gliomas are extremely aggressive brain tumors with a very poor prognosis. One of the more promising strategies for the treatment of human gliomas is targeted immunotherapy where antigens that are unique to the tumors are exploited to generate vaccines. The approach, however, is complicated by the fact that human gliomas escape immune surveillance by creating an immune suppressed microenvironment. In order to oppose the glioma imposed immune suppression, molecules and pathways involved in immune cell maturation, expansion, and migration are under intensive clinical investigation as adjuvant therapy. Toll-like receptors (TLRs) mediate many of these functions in immune cell types, and TLR agonists, thus, are currently primary candidate molecules to be used as important adjuvants in a variety of cancers. In animal models for glioma, TLR agonists have exhibited antitumor properties by facilitating antigen presentation and stimulating innate and adaptive immunity. In clinical trials, several TLR agonists have achieved survival benefit, and many more trials are recruiting or ongoing. However, a second complicating factor is that TLRs are also expressed on cancer cells where they can participate instead in a variety of tumor promoting activities including cell growth, proliferation, invasion, migration, and even stem cell maintenance. TLR agonists can, therefore, possibly play dual roles in tumor biology. Here, how TLRs and TLR agonists function in glioma biology and in anti-glioma therapies is summarized in an effort to provide a current picture of the sophisticated relationship of glioma with the immune system and the implications for immunotherapy.

Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression

“…This is essential information that may help explain the alterations in the immune system within GBM and reveal TLR-dependent interventions for follow-up studies. Moreover, this information may be useful in activating the immune system for complementary immunotherapy approaches, as exposure to TLR ligands is currently one approach being assessed (Deng et al, 2014). …”

“…Given the importance of EGFR in GBM progression (Brennan et al, 2013) and CSC self-renewal (Mazzoleni et al, 2010), the activation of MyD88-dependent or -independent pathways may provide diametrically opposite results. Furthermore, clarifying this difference will be vital information as TLR modulation is being explored as an adjuvant immunotherapy for brain tumors (Deng et al, 2014). …”

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

“…TLRs are also expressed on various immune cells, including T and B cells [36, 37], dendritic cells (DCs) [38], macrophages [39] as well as some non-immune cells such as fibroblasts and epithelial cells [40]. Upon encounter with specific microbial molecules TLR receptor are activated and initiate downstream signaling via MyD88-dependent or -independent pathways [41]. The identification of TLRs advanced the field of immunoadjuvants greatly, as most microbial immunoadjuvants work through TLR ligands [30], [42, 43].…”

“…TLR9 has an inverse effect in neuroblastoma cells in vitro and in vivo , as evidenced by reduced proliferation and increased apoptosis [52]. Intriguingly, TLRs that are expressed on immune cells are also expressed by glioma cells, and the same TLRs (TLR2, TLR4 and TLR9) have a tumor-promoting role in the biology of these tumors [41]. As gp96 expression is increased in multiple malignant cancers [53], it suggests gp96-regulated TLR signaling to be involved in cancer oncogenesis.…”

“…Indeed, immunotherapy is one of the more promising therapeutic strategies for the treatment of human gliomas. In 2010, a CpG phase II clinical trial was completed for patients with recurrent glioblastoma multiforme (GBM), where the therapy was well tolerated and a modest increase in survival rate was observed [41]. Since gp96 is an essential chaperone for nearly all of the TLRs, it logically follows that gp96 has a key role in potentiating TLR functions in adjuvant therapies.…”