Dendritic Cells and Cancer Immunity

Abstract

Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors. Bypassing suppressive pathways or directly activating DCs can unleash a T-cell response, and although clinical efficacy has proven elusive, therapeutic targeting of DCs continues to hold translational potential in combinatorial approaches.

Keywords: antigen presentation; cancer; dendritic cells; immunotherapy; tumor microenvironment; vaccination.

Figure 1. Dendritic Cell Differentiation

Dendritic cells (DCs) are part of the hematopoietic cell lineage, originating from hematopoietic stem cells (HSC), which subsequently differentiate into common myeloid progenitors (CMPs). The transcription factor Nur77 drives the differentiation of CMPs through several steps into monocytes, which can further differentiate into monocyte DCs (moDCs) under inflammatory conditions. In the absence of Nur77, CMP will differentiate through multiple stages into a common dendritic cell progenitor (CDP). The conventional type 1 DC (cDC1), conventional type 2 DC (cDC2) and plasmacytoid DC (pDC) subsets arise from the CDP, with the critical transcription factors shown for each lineage. Markers for each DC subset are shown on the right for mouse (black) or human (green). cDC1 in mice can be identified by expression of either CD8 α in the lymphoid organs or CD103 within peripheral tissues.

Figure 2. DCs in Anti-Tumor Immunity

Conventional type 1 dendritic cells (cDC1) are necessary for the generation of a de novo T cell response against tumors. Expansion of cDC progenitors occurs in the bone marrow driven by FMS-related tyrosine kinase 3 ligand (Flt-3L) (1). These cells differentiate into immature cDC1 within tissues, including tumors as depicted here. There, they can acquire antigens but are unable to stimulate T cells (2). DC activation/maturation is driven by damage-associated molecular patterns (DAMPs) released from necrotic cells and/or type I interferons (IFNs) released by cells within the tumor microenvironment (3). A subset of mature cDC1 expressing CCR7 migrate to the lymph node (4) where they prime a CD8⁺ T cell response (5). Activated T cells may then migrate to the tumor site – depending on the condition of the vasculature and stroma – where they can mediate their cytotoxic effector function (red X). Non-migratory cDC1 that remain in the tumor may interact with CD8⁺ T cells to regulate the anti-tumor response, with cDC1 secreting interleukin-12 (IL-12) or other cytokines to promote T cell effector function (6). Under ideal conditions this may release additional tumor antigens and DAMPs, and increase expression of inflammatory cytokines, further augmenting an immune response.