What is the role of toll-like receptor activation in immunotherapeutic targeting in pediatric oncology?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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A total of 13 TLRs have been identified in humans, each binding 1 or more specific TLR ligands. [15] TLRs can be activated by proteins that are released by or associated with pathogens (ie, lipopolysaccharide, double-stranded RNA, double-stranded DNA) or released by proteins exposed by tissue damage. Although pathogen-derived TLR ligands are well characterized, elucidation of TLR ligands derived from self-tissues continues.

The therapeutic potential of TLR-targeted therapies has been realized in 2 adult cancers by using the cell-wall skeleton of bacillus Calmette-Guérin (BCG-CWS), a TLR2 and TLR4 agonist, in the treatment of bladder cancer, [16] and using imiquimod, a TLR7 agonist, in the treatment of basal cell cancer. [17] Clinical trials are ongoing in several other adult malignancies, but preliminary results suggest that these may not be sufficient as single agents to induce regression of established bulky tumors. [17]

Such therapies have not yet made their way into pediatric oncology clinical trials, but this may change. Several animal models of pediatric tumors have responded to CpG oligodeoxynucleotides, a TLR9 agonist, including acute myelogenous leukemia (AML), lymphoma, neuroblastoma (see the image below), and rhabdomyosarcoma. [18] Aluminum salts, an adjuvant with TLR4 agonistic properties, have been engineered into vaccines used in children (eg, human papillomavirus vaccine) to augment immune responses and prevent development of secondary cervical cancer. [17]

Histologic subtypes of neuroblastoma. Top right pa Histologic subtypes of neuroblastoma. Top right panel, neuroblastoma: A monotonous population of hyperchromatic cells with scant cytoplasm. Bottom left panel, ganglioneuroblastoma: Increased schwannian stroma. Bottom right panel, ganglioneuroma: Mature ganglion cell with schwannian stroma.

Tumor cells can also release or expose damage-associated molecular patterns, which include lipids and lipopeptides, proteins, and nucleic acids that bind to TLRs and cause activation of macrophages and dendritic cells (DCs). [17]

The release of inflammatory mediators by damaged cells also plays a central role in amplifying and directing specific T-cell responses. Recent studies have investigated the contribution of such damage-associated molecular patterns in the antitumor effects seen with more conventional cytotoxic therapies. For instance, deficiency of TLR4 compromises the efficacy of chemotherapy or radiotherapy in vivo. [19]

Moreover, tumor irradiation has been recently hypothesized to activate effectors of innate immunity through the induction of tumor-cell apoptosis and the release of endogenous TLR agonists, such as heat-shock proteins, uric acid, or high-mobility group box protein 1 (HMGB1). Whether this relates solely to release of damage-associated molecular patterns by dying eukaryotic cells or is an indirect effect of mucosal damage with systemic seeding of bacteria remains unclear.

Whole-body irradiation was recently shown to increase bacterial translocation and circulating levels of the TLR4 agonist lipopolysaccharide. [14] This platform has been shown in a preclinical model to enhance the effectiveness of adoptively transferred CD8+ T cells in tumor-bearing, lympho-depleted mice, leading to improved tumor regression, whereas tumor-bearing mice deficient in TLR4 do not benefit from whole body irradiation. [20]

Thus, although radiation may have been traditionally viewed as a purely cytotoxic therapy to shrink tumors, it may also have significant immunomodulatory properties.

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