Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

Abstract

The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.

Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition

“…Although ex vivo generated moDCs are widely used for immunotherapeutic approaches (17,23,25,34,37) their efficacy in including desired anti-tumor responses still needs to be improved (15,23,38). For example, the efficiency of tumor antigen loaded matured moDCs to migrate and settle into lymph nodes is not fully accomplished, since the majority of moDCs does not reach the lymph node (122).…”

“…This population is regularly referred to as monocyte-derived DCs (moDCs), inflammatory DCs, or Tip DCs in the literature (16,22,23). In contrast to cDCs, monocytes exhibit a high frequency in human blood rendering them an interesting tool for the generation of vast moDC numbers for autologous cell transfer approaches (23)(24)(25). Further, the combination of robustness, functional parallels to primary DCs, and availability emphasize the application of moDCs as a model system to gain a general overview in new aspects of DC biology (26,27).…”

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells

“…In addition, B-1 cells [17,28] and myeloid cells [85], which are targeted via CR-3, may exert on one hand elevated innate responses, like phagocytosis, and on the other hand, acquire APC activity, and thereby contribute to the overall induction of cellular immune responses. DC [86] and B cells [87] that engage the nano-vaccine will also induce Th cells, which in turn activate CD8 + T cells [88] and B cells [89]. Follicular dendritic cells (FDC) contribute to affinity maturation and memory B cell induction and survival [90] by long-term storage of complement-opsonized immune complexes [90] that are internalized via CR1/2 [91].…”

“…In addition, B-1 cells [ 17 , 28 ] and myeloid cells [ 85 ], which are targeted via CR-3, may exert on one hand elevated innate responses, like phagocytosis, and on the other hand, acquire APC activity, and thereby contribute to the overall induction of cellular immune responses. DC [ 86 ] and B cells [ 87 ] that engage the nano-vaccine will also induce Th cells, which in turn activate CD8 + T cells [ 88 ] and B cells [ 89 ].…”

Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment

“…Here, we summarize our current knowledge on the role and interaction of dendritic cells (DCs) and natural killer (NK) cells in the tumor microenvironment (TME). While circulating NK cells are efficient at identifying and eliminating tumor cells, DCs bridge the innate and adaptive immune system via the uptake of tumor cell debris and the subsequent presentation of tumor-specific antigens to T cells (1). NK cells and DCs are currently used for immunotherapies to treat tumor patients, for NK cells exhibit the ability to directly eliminate tumor cells without prior sensitization, while DCs are able to initiate an immune response by presenting antigens and inducing tumor-antigen specific CD8 + T cell (2).…”