Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

Abstract

Tumor-infiltrating CD8⁺ T cells have been shown to play a crucial role in controlling tumor progression. However, the recruitment and activation of these immune cells at the tumor site are strictly dependent on several factors, including the presence of dendritic cells (DCs), the main orchestrators of the antitumor immune responses. Among the various DC subsets, the role of cDC1s has been demonstrated in several preclinical experimental mouse models. In addition, the high density of tumor-infiltrating cDC1s has been associated with improved survival in many cancer patients. The ability of cDC1s to modulate antitumor activity depends on their interaction with other immune populations, such as NK cells. This evidence has led to the development of new strategies aimed at increasing the abundance and activity of cDC1s in tumors, thus providing attractive new avenues to enhance antitumor immunity for both established and novel anticancer immunotherapies. In this review, we provide an overview of the various subsets of DCs, focusing in particular on the role of cDC1s, their ability to interact with other intratumoral immune cells, and their prognostic significance on solid tumors. Finally, we outline key therapeutic strategies that promote the immunogenic functions of DCs in cancer immunotherapy.

Keywords: CD8+ T-cells; DC-NK cell axis; dendritic cells; solid tumors.

Figure 1

Activity of dendritic cell (DC) subsets in cancer immunity. In the TME, DCs can have both an anti-tumor and pro-tumor effect. Anti-tumor activity is mainly driven by cDC1s and cDC2s (left panel). cDC1s induce recruitment and activation of CD8⁺ T lymphocytes in the TME through cytokine production and cross-presentation of tumor antigens, respectively. cDC2s are the major activators of CD4⁺ T cells. moDCs act mainly by stimulating cDC1s and cDC2s, whereas pDCs kill tumor cells through the expression of IFN-α/β, TRAIL and Granzyme B (GZMB). moDCs and pDCs may also have a pro-tumor action by creating an immunosuppressive environment and promoting tumor growth (right panel). moDCs produce molecules with immunosuppressive function such as iNOS, TNFα, IL-6 and IL-10. pDCs secrete chemokines able to recruit Tregs into the TME (CCL22 and IDO) as well as pro-angiogenic cytokines (TNFα, IL-8, and IL-1α).

Figure 2

DCs-NK cells cross-talk in cancer immunity. (A), DCs, NK cells and CD8⁺ T cells interact with each other in the TME. (B), Loop of maturation of DCs by HMGB1 produced by NK cells and activation of NK cells by IL-18 released by DCs. (C), Ability of cDCs to increase IFN-γ production by NK cells and amplify their anti-tumor activity either by a cell-cell contact mechanism or by release of the cytokines IL-12 and IL-15. (D), Recruitment and survival of cDCs are dependent on the chemokines CCL5, XCL1/2 and FLT3L produced by NK cells. (E), CXCL9 and CXCL10 chemokines released by DCs are crucial for both recruitment and activation of NK cells and CD8⁺ T cells in the TME. (F), Significant correlations between the genetic signatures of cDC1s, NK cells and CD8⁺ T cells and the key molecules involved in the interaction between cDC1s and NK cells are essential for stratifying low- and high-risk cancer patients.