Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells' unique role in the initiation of immune responses and the induction of tolerance.

Antigen Presentation and T Cell Stimulation by Dendritic Cells

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

/pdf/classification-of-current-anticancer-immunotherapies-3bquq660nx.pdf

Classification of current anticancer immunotherapies

Biodegradable core−shell structured nanoparticles with a poly(β-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of ∼30%. Particles loaded with mRNA administered intranasally (i.n.) in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a time point when naked mRNA given i.n. showed no expression. At later time points, luciferase expres...

/pdf/in-vitro-and-in-vivo-mrna-delivery-using-lipid-enveloped-ph-58ezvcikxj.pdf

In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles.

DCs1 are antigen-presentin g cells that regulat e several components of the immune system. The mature or terminal stage of DC developmen t induces specific T-cell immunity and resistanc e to experimenta l tumors in vivo. However, DC maturation is induced by inflammator y and microbial stimuli, so it isunlikely that mature DCsnormally present antigens from tumor cells in cancer patients. Accordingly, clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients. This approach has the potential to control response s to cancer antigens in a specific and nontoxic manner , in both vaccination and therapeuti c settings. DCs can mobilize several immune resistanc e mechanisms. These include CD8 CTLs, CD4 helper T cells, NK and NKT cells. Each of these lymphocytes recognizes target s through a distinct mechanis m and has the capacit y to kil l tumor cells and release valuabl e protective cytokines like IFN-g. CD4 T cells also provide essentia l help for the expansion and maintenanc e of CD8 cytolytic cells, while NK and NKT cells can eliminate target s that dampen presentatio n on MHC class I to escape CTL recognition. The stimulation and concerted action of these classes of lymphocytes can now be studied directly in patients, using ex vivo–derived DCs. Several findings have emerged from studies of healthy volunteers who have been immunized with DCs charged with model antigens, KLH protein and influenza virus matrix peptide. Mature DCs elicit a polarized Th1 type of CD4 T-cell response , only a single injection being required. Vaccination with antigen-bearing DCs also markedl y improves the functional affinity of CD8 T cells. These findings are important in the context of immunotherapy becaus e Th1 cells are more efficient helper cells in experimental model s of viral infection and tumors, while high-affinity CTLs shoul d improve recognition of tumor-derived peptides. An important caution also has surfaced when DCs are not adequately differentiated. Immature DCs can silence adaptive T-cell responses , e.g., by inducing IL-10–producing, T-reg cells. DC-based active immunization does not resul t in major shortterm toxicity in healthy subject sor cancer patients. Tumor-specific T-cell response s have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune response s observed in the first protocol s are still smaller than those seen naturall y in acute viral infections. Occasional clinical regression s have been noted in these initial feasibility studies, particularl y in melanomas , pediatri c tumors, lymphomas, prostat e cancer s and renal cell cancers . This information, coupled with progres in DC biology, suggest s many ways to improve the efficacy of this new therapy. Some relevant topics include antigen loading and DC maturation procedures , frequency and route of DC injection, efficiency of DC homing to lymphoid tissues and their longevity once there and the role of distinct DC subsets . A valuabl e positive control in active immunization protocols is to include an aliquot of DCs pulsed with a viral peptide to verify that the DCs and the patient’s immune system are measurabl y competent. Most of the first vaccination protocol s have used DCs charged with synthetic, HLA-binding tumor peptides. Many methodsare in place to allow DCs to proces abroader array of peptides appropriate for the patient’s MHC haplotype. These include transfection (RNA, DNA and viral vectors) , select pathways of adsorptive endocytosis , exosomes and tumor cell fusion. An intriguing new approach involves the processing of whole tumor cells. Immature DCs are able to internalize tumor cells, including melanoma, EBV lymphoma and prostat e carcinoma cell lines. Following maturation, theprocessing of tumor cells leads to presentatio n of multiple epitopes on both MHC class I and II product s of DCs. Basic issues in human cancer immunology can be investigated with ex vivo–based DC immunization. Some topics for the near future are the extent to which tumor-specific tolerance is an obstacl e to immunetherapy and theneed to mobilizeseveral adaptive and innate mechanisms in tandem, including Th1 type CD4 helper T, NK and NKT cells. Progres is also being made in manipulating DCsdirectly in vivo. Thiswil l help to design vaccine adjuvant s that improve presentatio n of tumor cells in patients. Although tumorschallengetheimmunesystem in formidableways relative to infectious diseases , it is now feasibl e to use active immunotherap y and DC biology to manipulat e and study the human respons e to cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.1503

Active immunization against cancer with dendritic cells: the near future.

Polycations that absorb protons in response to the acidification of endosomes can theoretically disrupt these vesicles via the “proton sponge” effect. To exploit this mechanism, we created nanoparticles with a segregated core−shell structure for efficient, noncytotoxic intracellular drug delivery. Cross-linked polymer nanoparticles were synthesized with a pH-responsive core and hydrophilic charged shell designed to disrupt endosomes and mediate drug/cell binding, respectively. By sequestering the relatively hydrophobic pH-responsive core component within a more hydrophilic pH-insensitive shell, nontoxic delivery of small molecules and proteins to the cytosol was achieved in dendritic cells, a key cell type of interest in the context of vaccines and immunotherapy.

/pdf/cytosolic-delivery-of-membrane-impermeable-molecules-in-3mr3vsb5i3.pdf

Cytosolic delivery of membrane-impermeable molecules in dendritic cells using pH-responsive core-shell nanoparticles.

Immunization with dendritic cells (DCs) transfected with genes encoding tumor-associated antigens (TAAs) is a highly promising approach to cancer immunotherapy. We have developed a system, using complexes of plasmid DNA expression constructs with the cationic peptide CL22, that transfects human monocyte-derived DCs much more efficiently than alternative nonviral agents. After CL22 transfection, DCs expressing antigens stimulated autologous T cells in vitro and elicited primary immune responses in syngeneic mice, in an antigen-specific manner. Injection of CL22-transfected DCs expressing a TAA, but not DCs pulsed with a TAA-derived peptide, protected mice from lethal challenge with tumor cells in an aggressive model of melanoma. The CL22 system is a fast and efficient alternative to viral vectors for engineering DCs for use in immunotherapy and research.

Efficient nonviral transfection of dendritic cells and their use for in vivo immunization.

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Efficient nonviral transfection of dendritic cells and their use for in vivo immunization.