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Dendritic cells in cancer immunology and immunotherapy

Abstract

Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.

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Fig. 1: Induction of T cell-mediated immunity or tolerance by DCs.
Fig. 2: Regulation of DC function by tumours.
Fig. 3: DCs in the context of cancer therapy.
Fig. 4: Exploiting DCs for cancer immunotherapy.

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Acknowledgements

The authors thank all members of the D.S. laboratory at Centro Nacional de Investigaciones Cardiovasculares (CNIC) for scientific discussions. S.K.W. is supported by a European Molecular Biology Organization Long-Term Fellowship (grant ALTF 438–2016) and a CNIC–International Postdoctoral Program Fellowship (grant 17230–2016). F.J.C. is the recipient of a PhD ‘La Caixa’ fellowship. Work in the D.S. laboratory is funded by the CNIC, by the European Research Council (ERC Consolidator Grant 2016 725091), by the European Commission (635122-PROCROP H2020), by the Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R), by the Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM), by FIS-Instituto de Salud Carlos III, MCNU and FEDER (RD16/0015/0018-REEM), by Acteria Foundation, by Atresmedia (Constantes y Vitales prize) and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III, the MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505).

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Nature Reviews Immunology thanks V. Bigley, T. de Gruijl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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F.J.C. and S.K.W. contributed equally to this work and share first authorship. S.K.W. and F.J.C. prepared tables and figures and conceptualized and wrote the manuscript. A.M.M. and M.F.K. conceptualized and wrote part of the manuscript. I.M. helped with conceptualization and edited the manuscript. D.S. conceptualized and wrote the manuscript. All authors contributed to manuscript editing, and read and approved the final version.

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Correspondence to David Sancho.

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Competing interests

I.M. reports receiving commercial research grants from Bristol-Myers Squibb and Roche and serves as a consultant/advisory board member for Bristol-Myers Squibb, Merck Serono, Roche-Genentech, Genmab, Incyte, Bioncotech, Tusk, Molecular Partners, F-STAR, Alligator and AstraZeneca. The other authors declare no competing interests.

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Glossary

Pathogen-associated molecular patterns

(PAMPs). Conserved molecules expressed by microorganisms that activate host pattern recognition receptors to alert the immune system to the presence of infection.

Damage-associated molecular patterns

(DAMPs). Endogenous molecular motifs associated with host cell death and tissue damage that can activate the immune system via pattern recognition receptors.

Pattern recognition receptors

(PRRs). Germ line-encoded host sensors that detect pathogen-associated molecular patterns, although many of them have also been described to sense damage-associated molecular patterns. This interaction triggers signalling in the host cell.

Tumour microenvironment

(TME). Usually refers to the non-tumoural cells that surround tumour cells, including fibroblasts, blood vessels and immune cells as well as the milieu of extracellular factors such as cytokines, soluble molecules and extracellular matrix.

Tumour-associated antigens

(TAAs). Autologous cellular antigens generated in tumour cells. They can be the product of mutated genes, antigens produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins, differentiation antigens specific for a cell type and overexpressed or aberrantly expressed cellular proteins.

Cross-presentation

The presentation of exogenous antigens (which are typically presented on MHC class II antigens) on MHC class I molecules. It can occur through the vacuolar pathway, leading to loading of peptides onto MHC class I molecules in the phagosome. Alternatively, cross-presentation can involve the transfer of exogenously acquired antigens to the cytosol, where they are processed by the proteasome and degraded to peptides that are transported to the endoplasmic reticulum for loading on MHC class I molecules. The stimulation of naive cytotoxic CD8+ T cells following cross-presentation is known as ‘cross-priming’ and is needed for antitumour immunity.

Immunogenic cell death

A form of cell death that induces an effective immune response through activation of dendritic cells. Hallmarks include the exposure of calreticulin on the cell surface and the active release of high mobility group protein B1 (HMGB1). This is in contrast to silent apoptosis, which is not immunogenic.

Out-of-field or abscopal effects

The ability of localized irradiation or treatment of a tumour to trigger a systemic antitumour effect that can lead to rejection of distant tumours or metastases.

Immune checkpoint blockade

(ICB). Blockade of specific interactions between immune cells and cancer cells or other immune cells by targeting inhibitory molecules such as CTLA4, PD1 and PDL1 that dampen immune cell activation. Inhibiting these interactions releases the ‘brakes’ on the immune system and promotes immune cell activation.

Adjuvants

Charles Janeway described adjuvants as the ‘immunologist’s dirty little secret’, as they were substances added to antigens to make vaccines effective, but their mode of action was not known at that time. Adjuvants contain compounds that stimulate the immune system, frequently pathogen-associated molecular patterns acting on pattern recognition receptors.

Neoantigens

Antigens formed by peptides that are absent from the normal human genome. These neoepitopes can be derived from tumour-specific DNA mutations or from viral sequences in the case of virus-associated tumours.

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Wculek, S.K., Cueto, F.J., Mujal, A.M. et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol 20, 7–24 (2020). https://doi.org/10.1038/s41577-019-0210-z

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