Toll-Like Receptor Agonists: Current Status and Future Perspective on their Utility as Adjuvants in Improving Antic Ancer Vaccination Strategies

Baxevanis, Constantin N.; Voutsas, Ioannis F.; Tsitsilonis, Ourania E.

doi:10.2217/imt.13.24

Cited by 37 publications

(40 citation statements)

References 99 publications

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“…Although TLR agonists have often been used in experimental and clinical studies as an immune adjuvant [27], many are associated with significant side effects or toxicity [37,38]. FimH represents a recently discovered TLR4 ligand with a great potential to be a safe and effective immune modulator, particularly amenable for mucosal application based on its selective effect on APCs [39].…”

Section: Discussionmentioning

confidence: 99%

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.Keywords: DCs r Delayed Th1 immunity r FimH r Mycobacterium r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPulmonary mycobacterial infection is mainly caused by Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), and by other slow growing less virulent nontuberculous Correspondence: Dr. Zhou Xing e-mail: xingz@mcmaster.ca mycobacterial (NTM) species including M. avium and M. kasasii. The continuing high global incidence of and death due to tuberculosis infections [1] and the dramatic increase in pulmonary NTM disease globally over the past three decades [2] underscores the need to further understand the complex host immune responses to mycobacterial exposure in order to develop effective prophylactic and therapeutic strategies.Protective immunity against mycobacterial infection requires the presence of a robust adaptive Th1-type response at the site of Eur. J. Immunol. 2014Immunol. . 44: 1375Immunol. -1386 infection. Upon exposure to the bacterium, mycobacteria is taken up by sentinel APCs such as DCs and delivered to the draining lymph node (dLN) [3,4]. On arrival, these APCs present mycobacterial antigen to naive T cells within the dLN, thereby priming the antigen-specific T cells to a Th1 phenotype and stimulating their expansion [5]. The Th1 cells are then recruited back to the site of infection, and the secretion of Th1 cytokines such as IFN-γ by these cells is critical to activation of infected APCs to control bacterial growth [6]. However, one of the defining characteristics of host defense toward mycobacterial patho...

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Section: Discussionmentioning

confidence: 99%

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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“…[36][37][38] Stimulation of TLR on DC can also facilitate the induction of Th1 immune responses. 39,40 In a review of several vaccine studies for malignant melanoma, Engel-Noerregaard reported significantly higher response rates in patients who received adjuvants as a part of their vaccine regimen. 41 Poly-ICLC (Hiltonol) is an inosine and cytidine-rich double stranded RNA that stimulates TLR3 and activates DC through a TLR-domain containing adapter inducing interferon-b (TRIF).…”

Section: Adjuvant For DC Vaccinesmentioning

confidence: 99%

“…In three of these cases, adjuvant activity was definitively shown to activate the TLR pathway in DC. 47,49,51 More study is needed, however, because the role of TLR in DC activation has been extensively and recently reviewed 40,54 and one theme that has emerged is that TLR activation in murine models cannot be easily extrapolated to human models because murine and human DC constitutively express a different overlapping set of TLR. DC, exposed to antigen can be matured in vitro or in vivo.…”

Section: Adjuvant For DC Vaccinesmentioning

confidence: 99%

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

Elster

Krishnadas

Lucas

2016

Human Vaccines & Immunotherapeutics

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For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials.

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“…Therefore, the use of TLR agonists to mature DCs either ex vivo or in situ is an attractive method for initiating or promoting antitumor responses (Baxevanis et al, 2013). Lung cancer is the most common cause of death from cancer, as it is responsible for approximately 13.5% of all cancer deaths (Ferlay et al, 2007;Prado-Garcia et al, 2012), and the 5-year survival rate in lung cancer is less than 15% (Jemal et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa Mannose-Sensitive Hemagglutinin Promotes T-Cell Response via Toll-Like Receptor 4–Mediated Dendritic Cells to Slow Tumor Progression in Mice

Zhang

Luo

Zhang

et al. 2014

J Pharmacol Exp Ther

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Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) as a drug may kill tumor cells and has been used clinically. However, the antitumor immune response of PA-MSHA is not completely understood. In this study, we found that treating Lewis lung carcinoma (3LL)-bearing mice with PA-MSHA plus 3LL antigen led to slower tumor progression and longer survival. After PA-MSHA treatment, T-cell number and dendritic cell maturation were both increased significantly at the tumor site. In addition, PA-MSHA in vitro stimulation resulted in the maturation of bone marrow-derived dendritic cells (BMDCs) from naive mice, showing higher costimulatory molecule expression, more cytokine secretion, lower endocytic activity, and stronger capacity to enhance T-cell activation. Toll-like receptor (TLR)4 but not TLR2 was required in the maturation process. More importantly, PA-MSHA-induced DCs were essential for PA-MSHA to enhance activation, expansion, and interferon (IFN)-g secretion of TLR4-mediated T cells, which play a role in the antitumor effect of PA-MSHA. Thus, this study reveals PA-MSHA as a novel TLR4 agonist that elicits antitumor immune response to slow tumor progression.

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Toll-Like Receptor Agonists: Current Status and Future Perspective on their Utility as Adjuvants in Improving Antic Ancer Vaccination Strategies

Cited by 37 publications

References 99 publications

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

Pseudomonas aeruginosa Mannose-Sensitive Hemagglutinin Promotes T-Cell Response via Toll-Like Receptor 4–Mediated Dendritic Cells to Slow Tumor Progression in Mice

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