Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity

Abstract

Dendritic cells (DCs) are the sentinel antigen-presenting cells of the immune system; such that their productive interface with the dying cancer cells is crucial for proper communication of the "non-self" status of cancer cells to the adaptive immune system. Efficiency and the ultimate success of such a communication hinges upon the maturation status of the DCs, attained following their interaction with cancer cells. Immature DCs facilitate tolerance toward cancer cells (observed for many apoptotic inducers) while fully mature DCs can strongly promote anticancer immunity if they secrete the correct combinations of cytokines [observed when DCs interact with cancer cells undergoing immunogenic cell death (ICD)]. However, an intermediate population of DC maturation, called semi-mature DCs exists, which can potentiate either tolerogenicity or pro-tumorigenic responses (as happens in the case of certain chemotherapeutics and agents exerting ambivalent immune reactions). Specific combinations of DC phenotypic markers, DC-derived cytokines/chemokines, dying cancer cell-derived danger signals, and other less characterized entities (e.g., exosomes) can define the nature and evolution of the DC maturation state. In the present review, we discuss these different maturation states of DCs, how they might be attained and which anticancer agents or cell death modalities (e.g., tolerogenic cell death vs. ICD) may regulate these states.

Keywords: antigen; cancer; cell death; chemotherapy; cytokine; immunogenic cell death; immunosurveillance; phenotypic DC maturation.

Figure 1

Schematic representation of different states of DCs interacting with different types of cancer cells. Live cancer cells and cancer cells undergoing non-immunogenic cell death keep the steady state DCs in an immature state devoid of strong up-regulation of phenotypic maturation ligands (CD80, CD86, CD83, MHC-II) and functional maturation (no or negligible amounts of immunostimulatory cytokines). In certain ex vivo conditions, immature DCs can behave like natural killer DCs (NKDCs) or interferon-producing killer DCs (IKDCs), which can exert in vitro anticancer cytotoxicity. On the other hand, freeze/thawing of cancer cells, certain immunogenic live cancer cells, and certain therapy-induced non-immunogenic cell death routines can induce a “limbo” state in DCs called semi-mature DCs which are not fully mature and can be either devoid of phenotypic maturation ligands or functional maturation depending on the context. Both immature DCs and semi-mature DCs cause T cell anergy and facilitate tolerogenicity thereby compromising anticancer immunity. These DCs may also actively facilitate pro-tumorigenic signaling. However, some therapeutic paradigms can induce immunogenic cell death (ICD) or at least a certain level of augmented immunogenicity in cancer cells which causes the interacting DCs to fully mature. These fully mature DCs can potently elicit anticancer immunity. Fully mature DCs devoid of immunosuppressive cytokines like IL-10 can be termed as immunogenic DCs capable of forming the most productive interface with T cells to prime them for anticancer effector function. On the other hand, fully mature DCs secreting IL-23 (inflammatory DCs) may polarize the T cells toward a state where they have a “helper” behavior accompanied by IL-17 production (Th17). The role of Th17 cells in cancer immunity and progression is enigmatic and controversial.