Trends in Immunology
ReviewSeries: The Biology of Antigen PresentationDendritic Cells and Cancer Immunity
Section snippets
Dendritic Cells in Cancer
The preferential ability of conventional dendritic cells (cDCs) to activate T cells is the foundation of the ‘cancer immunity cycle’ outlined by Chen and Mellman [1]. Tumor-associated cDCs are thought to endocytose dead neoplastic cells or cellular debris and transport cancer-associated antigens to the draining lymph node where T-cell priming and activation can occur. Although multiple other professional antigen-presenting cells exist, including other DC subsets (Box 1), cDCs are particularly
Antigen Delivery and Presentation
cDCs exist as resident lymphoid tissue cDCs in the spleen and lymph nodes critical for sampling blood and lymph-born antigen, respectively, and as nonlymphoid tissue cDCs that can directly transport antigen from the peripheral tissues 2, 3. The relative importance of lymphoid versus nonlymphoid tissue cDCs in distributing and presenting antigen is highly context specific, depending on both the type of antigen and route of exposure. For example, infection models have been used to demonstrate the
Activation of Tumor DCs
Based on the reduced capacity of tumor-associated CD11c+ cells to induce T-cell proliferation, DCs within the tumor microenvironment have often been viewed as tolerogenic or immunosuppressive [27]. As discussed, however, it is the rare cDC1 subset that is required for CD8+ T-cell activation, and it is only recently that this population has been evaluated within tumors (Box 2). Indeed, while the dominant CD11c+ population of macrophages is incapable of activating CD8+ T cells, both tumor
Suppression of Tumor DCs
Several features distinguish immunogenic from nonimmunogenic tumors. The frequency of neoantigens appears to be a major determinant, based on the importance of immunoediting as well as the relationship between mutational burden and response to immune checkpoint blockade 51, 52, 53, 54. As discussed earlier, a second factor may be the degree of DC maturation that results from the type and extent of cell death within tumors. A third factor is likely the level of local and systemic immune
Nonmigratory Tumor DCs
The primary function of cDCs in cancer immunity is to sequentially acquire tumor antigen, migrate to the lymph node, and activate a de novo T-cell response (Figure 2). However, only a small fraction of tumor cDCs will end up migrating to the lymph nodes, possibly related to controlled expression of CCR7 [12]. This raises the possibility that the remaining cells may be involved in regulating the local immune microenvironment. It has already been described in the skin that clustering of
Vaccines
Therapeutic vaccination for cancer continues to be an active area of research and clinical investigation. However, as this has been expertly reviewed elsewhere [73], we will attempt only to highlight some key concepts here. All vaccines depend on the ability of DCs to act as antigen-presenting cells to T cells and can be classified by their approach into (i) nontargeted, (ii) in vivo targeted, or (iii) ex vivo loaded [73]. One of the first cancer vaccines to significantly advance in the clinic
Concluding Remarks and Future Directions
As inducers of a T-cell response, cDCs are the foundation of oncoimmunology, and it will likely become clear that they are critical for responses to cytotoxic and targeted agents as the immunological components of these treatments are uncovered. Although cDC activation has been thoroughly examined in the context of infection, our understanding of the signals driving activation under sterile conditions remains incomplete, as does our understanding of the immunosuppressive pathways within tumors
Acknowledgments
This work was supported NCI/NIH grant R00CA185325-02 and Moffitt Cancer Center's Shula Breast Cancer Award to B.R.
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