ROLEOF TLR-9 IN CANCER IMMUNITY
Intheir books FundamentalImmunityand Chemotherapy,Paul (2013) and Becker (2013) respectively define cancer and itsetiology, providing the basics of immunology and oncology. Since thispaper is centered on the role of TLR-9 in cancer immunity, O`Neill(2014), Hennessy, Parker and O`Neill (2014), Wang (2013), Wang R,Miyahara & Wang H, (2013) and Coussens & Werb (2013) explainhow TLR-9 influence the immunity of a host concerning the cancersthis paper is focused on. TLR-9 is signaled for activity by CpG ODN.Therefore, Piccinini & Midwood (2014), Mantovani et al. (2013)and Gonzalez et al. (2013) elucidate the PAMP and DAMP TLR signalingand how it affects the immunity of a host.
Roleof Toll-like Receptors 9 (TLR-9) in cancer immunity
Accordingto Becker (2013), cancer is one of the principal sources ofbereavement in our contemporary society. There are roughly 200different types of cancer. A recent study conducted in 2012 reportedthat there were 15.1 million new cancer cases, more than 9 millioncancer deaths and 33.7 million people living with cancer in 2013worldwide (p. 23). Cancer cells have the ability to elude immuneresponses, thereby promoting the development of tumor phenotypes andpathways that bypass the immune cells. The role of the immune systemin rebelling against cancer-causing agents (carcinogens) is an areaof exhaustive research. Cancer treatments like radiotherapy andchemotherapy could enhance continued existence nonetheless, severalpatients will have to tolerate metastasis and relapse, whichultimately lead to death. Furthermore, these cancer managementstrategies terminate both the cancerous and normal cells (Coussens &Werb, 2013, p. 860).
Therefore,a less toxic and more efficient treatment is warranted. Mantovani etal. (2013) observe that one of the most promising strategies isimmunotherapy, which uses the host`s immune system to fight themalignant cells. This is achieved through one of two waysstimulating the host`s immune system to attack the melanoma cells orthe elimination of the pathogen`s obstructing mechanisms to theimmune system (p. 772). One of the most possible approaches to themodulation of the body`s defenses is aiming PRRs in inborn immunesystems using proteins. Among some of the proteins in the humansystem that recognize conserved molecules in pathogens are Toll-likereceptors (TLRs) (O`Neill, 2014, p. 5). This paper examines the rolesof TLR-9 in cancer immunity.
Wang,Miyahara and Wang (2013) define TLRs as a family of evolutionarilypreserved transmembrane proteins that distinguish well-preservedmolecules on pathogens. TLR-9, as part of the inborn immune system,modulates the mechanisms that impact the development of adaptiveimmune responses. TLR-9 expressing cells are in the leading line ofdefense against invading microorganisms, triggering inborn immuneresponses (p. 182). In vivo and in-vitro researches on cancer haveproven the antitumoural activities in different types of cancer,signifying that these receptors are probable marks for cancerhealing. Moreover, TLR-9 plays a critical role in the regulation oftissue injury and wound healing and the regulation of apoptosis. TLRsact by recognizing PAMPs (Wang, 2013, p. 4987). PAMPs are conservedcomponents derived from fungi, viruses, bacteria and parasites. TLR-9also recognizes DAMPs in diseases that are similar to cancer. Todate, there are 10 known TLRs (TLR1-TLR10) in human beings, although13 have been identified in mice (Piccinini & Midwood, 2014, p.5).
Becauseof the activation of TLR-9, interferon-a, a protein that directlyinfluences the B cells` production of cytokine, is produced. Thisresults in anti-inflammatory cytokine release. At the onset ofactivation, CpG DNA is transferred by endocytosis to intracellularcompartments (Paul, 2013). This process of conveyance is not specificsince DNA sequences that do not have CpG dinucleotides can also bedistinguished by TLR-9. This manner of immune initiation can beinhibited by non-CpG sequences albeit competitively. The moment theprocess of transportation to intracellular compartments is complete,acidic endosomal maturation takes place (Hennessy, Parker, &O`Neill, 2014). This process may be inhibited by agents that raisethe pH, like chloroquine. Ultimately, anti-inflammatory cytokines arereleased, and the proliferation of the B cell is successfullyenhanced (Mantovani et al., 2013, p. 775).
Goalsof the study
Althoughchemotherapy and radiotherapy have proven to be beneficial to thesurvival of cancer patients, their utilization tags along detrimentaleffects like metastasis and relapse. As a result, the latest researchinto boosting the innate immunity of a patient has led to theintroduction of TLRs therapy to manage cancerous cells (Coussens &Werb, 2013). Therefore, this study pursues a comprehension of whatrole TLR-9 plays in cancer through the lens of three types ofcancers. I have chosen three so as to explore comparatively how TLR-9works across these three cancers and come up with robust inferencesabout its exact role. Consequently, this study seeks to find answersto the following questions
Whatis the role of TLR-9 in breast cancer?
Whatis the role of TLR-9 in prostate cancer?
Whatis the role of TLR-9 in lung cancer?
Sincethis is a relatively new field of scientific development, all thetest victims utilized in the articles I chose were not human. Theywere rats and other lab animals. I noticed too that no new scientificmethods were used. The rats and mice were grouped into two, withone-half being inoculated with a carcinogenic agent while the othergroup was not. After a while, half of the inoculated mice were placedon TLR-9 targeted therapy while the other half of the same inoculatedmice were not. After some time, qualitative conclusions were drawnfrom all the mice to determine whether TLR-9 has substantially actedon the innate immunity of the mice on TLR-9 therapy and those not onany form of treatment. The subsequent section of this paper explainsthe roles of TLR-9 in each of the three cancer types this paper iscentered on, though not limited to them.
Roleof TLR-9 in breast cancer immunity
TLR-9is a DNA receptor that distinguishes vertebrate and infectious DNA.Just like other TLRs, TLR-9 is located at the resting cell’sendoplasmic reticulum. When microbial, viral or fungal DNA enters thebreast cells, TLR-9 translocates to lysosomal/endosomal compartmentswhere ligand recognition and binding takes place (Gonzales et al.,2013, p. 865). The process of DNA recognition starts a downstreammotioning flow, which contains MyD88, an adaptor particle. AnNF-Kb-mediated inflammation is induced by the stimulation of TLR-9and is characterized by an amplified expression of several cytokinesas well as interleukins. MDA-MB-231, the mice breast cell lineseasoned for breast cancer, was found to express TLR-9 at both theprotein and the mRNA levels (Gonzales et al., 2013, p. 868).Therefore, the activation of TLR-9 was revealed to be exceedinglyeffective in breast cancers, with its signaling trail discovered tobe very responsive to breast malignant cells by constraining theprocess of cell multiplication (Coussens & Werb, 2013, p. 863).Furthermore, flagellin secretes a variety of soluble factors thatwere proven to inhibit the progression of breast tumors in anautocrine manner.
Roleof TLR-9 in prostate cancer immunity
Althoughthe functions of TLR-9 in prostate cancer treatment are still scanty,research is still being done to unravel the mysteries of the workingof TLR-9. Investigations into the TLR-9 stimulation were performed onmice epithelial cell PC3. When the PC3 cells express TLR-9, themembrane activates NF-kB leading to the secretion of cytokine IL-8(Hennessy, Parker & O`Neill, 2014). Becker (2013) points out thatTLR-9 is substantially expressed in C4-2B and LNCaP cells while it ismoderately expressed in Du-145 and PC3 (p. 299). The TLR-9 ligandcomprising of unmethylated oligonucleotides (CpG-ODN) and microbialDNA prompt the invasion of PCa cells through MMP-13. It was proventhat in preserved prostate epithelial cells capable of articulatingTLR-9, CpG-ODN led to the activation of NF-kB, increasing oppositionagainst TNF-alpha-prompted apoptosis. Therefore, it is evident thatTLR-9 signaling and pathways directly inhibit tumor growth or improveimmunotherapy in patients suffering from prostate cancer (Mantovaniet al., 2013, p. 775).
Rolesof TLR-9 in lung cancer immunity
Recently,it was revealed that TLR-9 prompted type 1 interferons that mediatedthe anti-inflammatory actions in the lungs of rats (O`Neill, 2014, p.18). Prompting of the TLR-9 articulating cell lines CpG-ODN with HeLaand A549 exposed noticeable antiapoptotic effects. In addition tothis, the activation of TLR-9 significantly heightened the dischargeof MCP-1 from the mice cell specimens upon stimulation by CpG-ODN asshown in vivo experiments (Paul, 2013, p. 196). However, theseanti-tumor effects were directly connected to an enhanced activity ofthe NK cells. In a modest form of lymphoma, the immunostimulatoryconsequence of CpG-ODN was proven to be accountable for theanti-cancer effects. In disparity, CpG-ODN had no influence on theexistence of mice injected with the 38c13 B cell lymphoma (Wang,Miyahara & Wang, 2013). Furthermore, the cancer cells specimenA549 and HeLa when enthused by CpG-ODN showed steady exudation ofchemokine MCP-1. MCP-1 induces the boosted assembly of numerouscytokines with antitumoral activities in NK cells, monocytes, Bcells, dendritic cells, and macrophages (Wang, 2013).
Toll-likereceptors are a group of configuration acknowledgement proteins bestknown for their role in host defense against infection. Emergingevidence shows that TLR-9 plays a domineering part in thepreservation of tissue homeostasis through regulating inflammatoryand tissue repair responses to injuries. As the immunomodulatoryfunctions of TLR-9 are known, they have become a center ofimmunological, biological and therapeutic research. TLR-9 plays apivotal role in a host’s inborn and adaptive immunity. CpG-ODNinitiates a signaling cascade, which is a complex trail that coverscountless steps, comprising the production of interferons and thesynthesis of proinflammatory cytokines, and consequently, noteworthyactivation of T-lymphocytes and pDCs. The stimulation of TLR-9induces an NF-Kb-facilitated inflammation, described by an amplifiedexpression of different cytokines and interleukins (Wang, 2013).
Therefore,the activation of TLR-9 was established to be greatly effective inbreast cancers, and its motioning path was discovered to be veryreactive to breast tumor cells by obstructing cell multiplication. Inmice inoculated with prostate carcinogens, activation of TLR-9 by CpGODN on cell line PC3 activates NF-kB, causing to the excretion ofcytokine IL-8 (Gonzalez et al., 2013). The activation of NF-kBaugments the struggle against TNF-alpha-induced apoptosis. Therefore,it is evident that TLR-9 signaling and pathways directly inhibittumor growth or improve immunotherapy in patients suffering fromprostate cancer (Paul, 2013). It is also apparent that in ratsinoculated with carcinogenic lung substances, TLR-9 prompted type 1interferons that facilitate the anti-inflammatory effects in lungs ofmice (Wang, Miyahara & Wang, 2013).
Promptingof the TLR-9 articulating cells HeLa with CpG-ODN and A549 exhibitednoticeable antiapoptotic effects against cancerous cells. Theadaptive immune system is the primary focus of the recentimmunological approaches in oncology. Endosomal Toll-like receptorsactivate immune responses by signaling DAMP (damage-associatedmolecular patterns) from decomposing tumor cells. This has led to thedevelopment of DNA-based TLR-9 agonists, which have anti-tumoractivities through adaptive and innate immune responses. Therefore,TLR-9 acts as mediators for the stimulation of the host`s immunesystem to attack cancer causing cells or to take away the pathogen`sinhibitory mechanisms to the immune system, boosting the host’simmune system against cancerous cells.
TLR-9-Toll-like receptors 9
CpG-ODN-Synthetic unmethylated Oligonucleotide
CpG-DNA-Synthetic unmethylated Deoxyribonucleic Acid
MRNA-Messenger Ribonucleic Acid
DAMP-Danger Associated Molecular Pattern
PAMP-PathogenAssociated Molecular Pattern
NF-Kb-Nuclear Factor-Kappa B
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