Volume 71, February 2024, 101848Author links open overlay panel, Abstract

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in shaping adaptive immunity. DCs have a unique ability to sample their environment, capture and process exogenous antigens into peptides that are then loaded onto major histocompatibility complex class I molecules for presentation to CD8+ T cells. This process, called cross-presentation, is essential for initiating and regulating CD8+ T cell responses against tumors and intracellular pathogens. In this review, we will discuss the role of DCs in cancer immunity, the molecular mechanisms underlying antigen cross-presentation by DCs, the immunosuppressive factors that limit the efficiency of this process in cancer, and approaches to overcome DC dysfunction and therapeutically promote antitumoral immunity.

Section snippetsHistory, definition, and function of dendritic cells

Dendritic cells (DCs) are phagocytes with the unique capacity to bridge innate and adaptive immunity [1], [2]. In 1973, Ralph Steinman, biologist at Rockefeller University, identified a rare subset of phagocytes, present in lymphoid organs [3], [4] and characterized by a unique cell morphology with multiple dendrites that he named “dendritic cells”. Ralph Steinman was awarded the Nobel Prize in Physiology or Medicine in 2011 for the discovery of DCs and the identification of their unique

Four types of cross-presentation mechanisms

Antigen cross-presentation is a process by which DCs acquire and process exogenous antigens into peptides that are then loaded on MHC class I molecules for presentation to CD8+ T cells [104], [105] (Fig. 2). This process is essential for initiating CD8+ T cell responses against tumors and intracellular pathogens [58], [106], [107]. The process of antigen cross-presentation by DCs can be divided into several key steps: antigen uptake, processing, and presentation on MHC class I molecules.

Immunotherapies to boost dendritic cell cross-presentation

Strategies to leverage DCs for immunotherapy [156], [157] and enhance antigen cross-presentation by cDC1 [158], [159] in the context of tumor immunity have shown promises in preclinical studies and early clinical trials. We’ll review two main approaches (Table 1): 1/ The development of “in situ” vaccines aimed at expanding the number of intratumoral cDCs, increasing uptake of antigens released by tumor cells in vivo, and enhancing DC maturation, and 2/ Therapeutic vaccines delivering antigens

Conclusion

Immunotherapy is revolutionizing cancer treatment. Although immune checkpoint inhibitors have shown great success, only a small fraction of cancer patients are responding to this treatment and novel immunotherapies complementing immune checkpoint blockade are needed. The critical role of DCs in the initiation and maintenance of immune responses against tumors make them important targets, especially for treatment of so called “immune desert” tumors devoid of T cell infiltration. This tumor

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are all employees of Genentech.

Acknowledgements

The authors thank Ira Mellman for his valuable comments on the manuscript.

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