Abstract
Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.
Highlights
Dendritic cells (DCs) function at the interface of the innate and adaptive immune systems, making them uniquely suited for cancer immunotherapy
We explore the biologic rationale for such multimodality approaches to optimize the impact of current DC-based cancer immunotherapy
In a murine B16-OVA melanoma model, combination therapy with dasatinib – a receptor tyrosine kinase (RTK) inhibitor targeting BCR-ABL, SRC, c-KIT, and platelet derived growth factor receptor (PDGFR) – and OVA-pulsed DC1 vaccines decreased tumor microenvironment (TME) levels of myeloid-derived suppressor cells (MDSC) and regulatory T-cell (Treg), enhanced TME recruitment of IL12p70producing DC1, and promoted a profound spreading in the repertoire of tumor-associated antigens recognized by CD8+ tumorinfiltrating lymphocytes (TILs) [63]
Summary
Dendritic cells (DCs) function at the interface of the innate and adaptive immune systems, making them uniquely suited for cancer immunotherapy. Beyond these approaches – reviewed extensively elsewhere [14] – our growing understanding of DC biology highlights potential strategies to improve DC-based vaccine efficacy: (a) exploiting diversity of DC lineage [i.e., plasmacytoid DCs [15], CD141+ DCs [16]] to improve antigen cross-presentation and potency of cytotoxic CD8+ T-lymphocyte (CTL) responses; (b) silencing of antigen presentation “attenuators” [e.g., inhibition of SOCS1 [17]] to enhance DC function by controlling the tolerogenic state of DCs and magnitude of antigen presentation; (c) synergizing with adoptive cell therapy [e.g., DC vaccine-primed peripheral blood T-cells expanded ex vivo with CD3/CD28 co-stimulation [18]]; (d) manipulating ex vivo DC maturation conditions to enhance immunogenicity [e.g., utilizing IL-15 to generate Langerhans-type DCs [19], or IFN-γ and lipopolysaccharide (LPS, a TLR4 agonist) to yield type 1-polarized DCs (DC1) [20]]; and (e) modification of co-stimulatory molecule expression to improve DC potency [e.g., mRNA-electroporated DCs encoding CD40L, CD70, and TLR4 [21]] Vaccine design must exploit such pre-programed cytokine secretion schedules in order to optimize in vivo DC efficacy
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