Dendritic cells and cancer immunotherapy
Introduction
Dendritic cells (DC) play a key role in initiating and maintaining immune responses. Since the discovery of DC by Ralph Steinman over 40 years ago [1] and the identification of their key function as mediators of T cell-mediated immune responses, there has been a major focus on the use of DC in cancer immunotherapy. DC have been used to vaccinate cancer patients for nearly 20 years [2••]. Until recently, most DC vaccines comprised DC or monocyte precursors of DC, isolated from the patient, loaded ex vivo with tumour antigen (Ag), and readministered to the patient. DC that migrated from the injection site to the draining lymph nodes were expected to prime naïve, and or boost memory, tumour-specific T cells capable of eradicating the tumour. To date, the majority of trials have been Phase I studies on small cohorts of advanced cancer patients who had failed to respond to conventional therapies. These trials revealed that this approach: (1) is feasible in many malignancies; (2) is well tolerated with minimal toxicity; and (3) can induce tumour-specific immune responses in many patients. Whilst early DC therapies resulted in limited clinical benefits, recent advances in our understanding of DC biology and new knowledge obtained from clinical trials have identified new strategies that are expected to improve clinical outcomes. Harnessing the unique capacity of different DC subtypes to drive specific immune responses in combinations with approaches designed to overcome tumour-mediated immune suppression and immune regulation, are emerging as key strategies for the development of new generation DC vaccines.
Section snippets
Can DC vaccines be of clinical benefit?
Early clinical studies showed a significant advantage of using DC vaccines over indirect vaccine approaches (e.g. naked peptides, recombinant proteins, tumour cells, viral vectors), with an objective response rate of 7.1% [3]. Since then we have learnt that immature DC generally induce tolerance rather than stimulate immunity, thus most trials now incorporate TLR ligands and or cytokines to specifically activate DC. The poor migratory capacity of early DC vaccines is being overcome by
Which DC subsets are important for anti-tumour immunity?
The emerging complexity of the DC network is an important consideration for the design of new generation DC vaccines. In human and mouse, multiple DC subsets exist that vary in location, phenotype and specialised function [7••]. They can be broadly classified as conventional DC (cDC), plasmacytoid DC (pDC) and inflammatory monocyte-derived (Mo) DC. The cDC can be further divided based on location into ‘lymphoid-resident’ and ‘migratory’ DC. The lymphoid-resident DC capture Ag directly from the
Exploiting DC pattern recognition receptors for cancer immunotherapy
DC subsets express a range of unique and shared pattern recognition receptors (PRR), including CLRs and TLRs that can be harnessed to enhance the efficacy of cancer immunotherapy (Figure 1) [31]. Monoclonal antibodies (mAbs) specific for CLRs can be used to target Ag directly to particular DC subset(s) in vivo [31, 32, 33]. This attractive approach circumvents the issues of poor DC migration and logistics associated with in vitro-manufactured, patient-specific vaccines, in addition to allowing
Enhancing immunogenicity of the tumour environment
One of the major impediments to the induction of effective anti-tumour responses is overcoming the suppressive nature of the tumour environment. Tumours employ cellular and soluble factors that directly suppress DC and T cell activation [49, 50], thus DC therapies need to be combined with mechanisms to boost the immunogenicity of the tumour environment, and enhance DC function. DC express PRR that recognise damage-associated molecular patterns (DAMPs), intracellular components revealed by dying
Overcoming immune regulation
One of the most exciting recent advances in cancer immunotherapy has been the development of Ab against negative regulators of T cell function, CTLA-4 and PD-1 [60, 61]. mAbs against both CTLA-4 and PD-1 induce strikingly high and durable clinical responses in melanoma and other tumours, but CTLA-4 treatment is accompanied by significant toxicity and adverse effects [60]. Combining DC immunotherapy with anti-CTLA-4 is feasible and well tolerated in advanced melanoma patients and induces a
Concluding remarks
In recent years, DC immunotherapy has moved from a simple concept of patient specific, in vitro generated vaccines towards a sophisticated approach of targeting Ag and activators to specialised DC subsets directly in vivo. The results of ongoing clinical trials using DEC-205 targeting in combination with TLR3 and TLR7/8 agonists are eagerly anticipated. Combining this approach with chemotherapy, radiotherapy or Ab against key immune checkpoint inhibitors will likely enhance efficacy by
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
MHL and KJR are supported by project grants from the National Health and Medical Research Council of Australia (NHMRC 604306 and 1025201) and the Prostate Cancer Foundation of Australia (PG2110). KJR holds a NHMRC CDF level 2 fellowship. KMT is the recipient of a University of Queensland International PhD Scholarship. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure
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