Review Article Volume 1 Issue 1 - April 2017 DOI: 10.19080/JTMP.2017.01.555554 J Tumor Med Prev Copyright © All rights are reserved by Damodar Gupta Role of Toll like Receptor(s) in Tumor Biology Sweta Sanguri and Damodar Gupta* Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine & Allied Sciences, India Submission: March 10, 2017; Published: April 24, 2017 *Corresponding author: Damodar Gupta, Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine & Allied Sciences, Brig. SK Mazumdar Marg, Defence Research and Development Organization, Ministry of Defence, Delhi 110054, India, Email: Abstract Toll like receptors belong to a family of specialized immune receptors that highly conserved and specific for their ligands. TLR signaling can identify specific pathogen and can induce expression of inflammatory cytokines, chemokines, initiate opsonization and phagocytosis, elicit reactive oxygen/nitrogen species production, activate the complement pathway etc. to get rid of it. Apart from its unquestionable role in pathogen recognition and neutralization, TLRs can also identify altered self-proteins including those expressed by transformed cell. Agonists of toll like receptors, both of natural or synthetic origin have been exploited for their ability to elicit and/or potentiate anticancer response alone or when combined with available treatment regimes. TLR agonist mediated activation of immune cells (lymphocytes, leukocytes etc.) and production of inflammatory mediators leads to the generation of cellular (adaptive) immune responses that hold promising applications against cancer progression. TLRs are expressed in cells of immune system including dendritic cells (DC) and macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes), and epithelial, endothelial, fibroblasts of different tissues. Tumor cells also express TLR, however, differential TLR expression in different cancer cell type leads to conflicting response(s) after activation with TLR agonists, which can be protumor or antitumor. TLR mediated inflammatory response(s), anti-apoptotic potential and epithelial regeneration properties may promote carcinogenesis. Moreover, several mechanisms including the induction of eT regs and abrogation of CTLs help the tumors evade cancer immune-surveillance. Therefore, a TLR agonist need to be selected for cancer therapy, based on the tumor microenvironment and a rigorous calculation of effects on immune cells, including T cell population (enhance effector and memory CTL activity, reduce eT reg function). Keywords: Toll Like receptors; TLR agonists; Cancer immunotherapy; TLR signaling; Tumor biology Abbreviations: TLR: Toll Like Receptors; PRR: Pattern Recognition Receptors; IL: Interleukins; PAMP: Pathogen-Associated Molecular Patterns; APC: Antigen Presenting Cells; DC: Dendritic Cells; CTL: Cytotoxic T Lymphocyte; eT regs : Effector T Regulatory cells; OV: Oncolytic Virus Introduction TLRs belong to the pattern recognition receptors (PRR) family that is known to sense both self and non-self danger signals [1]. They are crucial and important components of innate immune system, and act as first line of defence against different potential pathogens [2]. TLRs recognize broad classes of molecular structures including the lipopeptides, lipoteichoic acids, lipopolysaccharides, peptidoglycans, zymogens, mannans, flagellins, viral and bacterial nucleic acids etc. They initiate signal transduction cascades resulting in induction of inflammatory cytokines like the interferons, the interleukins- IL2, IL6, IL8, IL12, IL16, and TNF- α (as one of the responses) to get rid of unwanted organisms, pathogens and transformed self- tissues to maintain cellular homeostasis [3,4]. In addition, TLR signaling can trigger apoptosis, opsonization and phagocytosis, induction of reactive oxygen/nitrogen species, activation of the complement pathway etc. depending on the ligand (pathogen) sensed [5]. Furthermore, activation of TLRs is also known to activate intracellular signaling pathways resulting in activation of transcription factors including NFκB, MAPK etc. NF-κB regulates expression of anti-apoptotic genes, cytokines and growth factors [6]. Eleven different TLRs have been identified in humans till date and the TLR signaling is well studied and documented [7]. Various TLRs identified till date are summarized in Table 1 [8- 12]. TLRs also play an important role in the initiation of adaptive immune responses [13]. Pathogen (ligand) specific adaptive immunity develops due to activation of antigen presentation, TLR-dependent expression of pro inflammatory cytokines and up regulation of co-stimulatory molecules [14]. Moreover, T lymphocytes also express selective TLRs and can be directly activated by their respective ligands [15]. Toll-like receptors have also been shown to be an important link between innate and adaptive immunity [5,13,14]. TLR signaling plays differential role in maintenance of cellular homeostasis and the results include cell proliferation or J Tumor Med Prev 1(1): JTMP.MS.ID.555554 (2017) 0013