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Dendritic cells (DCs) are the most potent professional antigen presenting cells and are therefore indispensable for the control of immunity. The technique of antibody mediated antigen targeting to DC subsets has been the basis of intense research for more than a decade. Many murine studies have utilized this approach of antigen delivery to various kinds of endocytic receptors of DCs both in vitro and in vivo. Today, it is widely accepted that different DC subsets are important for the induction of select immune responses. Nevertheless, many questions still remain to be answered, such as the actual influence of the targeted receptor on the initiation of the immune response to the delivered antigen. Further efforts to better understand the induction of antigen-specific immune responses will support the transfer of this knowledge into novel treatment strategies for human diseases. In this review, we will discuss the state-of-the-art aspects of the basic principles of antibody mediated antigen targeting approaches. A table will also provide a broad overview of the latest studies using antigen targeting including addressed DC subset, targeted receptors, outcome, and applied coupling techniques.

Effective immune responses in both the spleen and the tumor microenvironment are crucial for cancer immunotherapy. However, delivery of neoantigen peptide vaccines to antigen‐presenting cells (APCs) at these sites remains challenging. In this study, LNPsD18, a cationic liposomal formulation that targets and enhances APC uptake at both sites without modifying the targeting ligands is developed. By co‐delivering tumor‐specific neoantigens and a cholesterol‐coupled toll‐like receptor 9 (TLR9) agonist within LNP‐vaxD18, an approximately 60‐fold increase in dendritic cell uptake compared to neoantigen‐adjuvant mixtures is achieved. Intravenous administration of the liposome‐neoantigen peptide vaccine targets both the spleen and the tumor, boosting splenic DC activation, increasing M1‐type tumor‐associated macrophages, and elevating tumor cytokine levels. This reshapes the tumor microenvironment, enhancing IFN‐γ‐producing CD8+ T cells and TCF1+CD8+ T cells within tumors. These outcomes significantly inhibit established tumor growth compared to nontargeted lipid‐based nanovaccine formulations, resulting in improved survival in orthotopic hepatocellular carcinoma and colorectal cancer models. The findings highlight the importance of targeting APCs in both the spleen and tumors to optimize the therapeutic efficacy of liposome‐neoantigen vaccines in cancer treatment. LNPsD18, a cationic liposome that enhances antigen‐presenting cell uptake in the spleen and tumor without targeting ligands is developed. Co‐delivering neoantigens and a TLR9 agonist significantly improve DC activation, tumor immunity, and survival in liver and colorectal cancer models, demonstrating the importance of dual‐site APC targeting for cancer immunotherapy.

Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141 DCs (cDC1) and CD1c DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody-mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141 DCs, such a receptor for CD1c DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c DCs and enhances the cytokine secretion (namely TNFα, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches.

Abstract Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promises, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.

Recently, the chemokine receptor XCR1 has been found to be exclusively expressed on a subset of dendritic cell (DC) known to be involved in antigen cross-presentation. This review aims to summarize the known biology of the XCR1 receptor and its chemokine ligand XCL1, both in the mouse and the human. Further, any involvement of this receptor-ligand pair in antigen uptake, cross-presentation, and induction of innate and adaptive cytotoxic immunity is explored. The concept of antigen delivery to DC via the XCR1 receptor is discussed as a vaccination strategy for selective induction of cytotoxic immunity against certain pathogens or tumors.

While CAR-T cell therapy has been very successful for treating B cell malignancies, and more recently multiple myeloma, achieving clinical success for acute myeloid leukemia (AML) remains a significant challenge. The examination of current single-antigen targeting CAR-T cell studies for AML illustrates the challenges faced by this therapy: efficacy limitations arise from the heterogeneity of the disease, which often results in antigen escape and subsequent circumvention of single-antigen targeting CAR-T cells, while safety limitations are mainly due to undesired hematological toxicity stemming from the absence of an antigen specifically expressed on AML tumor cells and not on normal hematopoietic cells. This study offers a comprehensive analysis of the most relevant AML surface antigenic markers —CD123, CD33, ADGRE2, CLL-1, TIM-3, CD70, among others— along with their expression patterns across key cell types, including leukemic blasts, leukemic stem cells, hematopoietic stem cells and progenitors, adult blood cells, and other tissues. Additionally, a variety of strategies for developing CAR-T therapies with improved efficacy and specificity are explored, with dual-antigen targeting CAR-T cell therapies emerging as the most promising approach to overcome the major hurdles observed in single-antigen targeting CAR-T cell therapies. Overall, this review identifies dual-antigen targeting as a therapy holding great prospects in the search of an effective and safe therapeutic approach for AML patients.

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.

Dendritic cells (DCs) are antigen-presenting cells essential for the induction of adaptive immune responses. Their unprecedented ability to present antigens to T cells has made them excellent targets for vaccine development. In the last years, a new technology based on antigen delivery directly to different DC subsets through the use of hybrid monoclonal antibodies (mAbs) to DC surface receptors fused to antigens of interest opened new perspectives for the induction of robust immune responses. Normally, the hybrid mAbs are administered with adjuvants that induce DC maturation. In this work, we targeted an antigen to the CD8α or the CD8α DC subsets in the presence of CpG oligodeoxinucleotides (ODN) or bacterial flagellin, using hybrid αDEC205 or αDCIR2 mAbs, respectively. We also accessed the role of toll-like receptors (TLRs) 5 and 9 signaling in the induction of specific humoral and cellular immune responses. Wild-type and TLR5 or TLR9 knockout mice were immunized with two doses of the hybrid αDEC205 or αDCIR2 mAbs, as well as with an isotype control, together with CpG ODN 1826 or flagellin. A chimeric antigen containing the 19 kDa portion of the merozoite surface protein (MSP1 ) linked to the Pan-allelic DR epitope was fused to each mAb. Specific CD4 T cell proliferation, cytokine, and antibody production were analyzed. We found that CpG ODN 1826 or flagellin were able to induce CD4 T cell proliferation, CD4 T cells producing pro-inflammatory cytokines, and specific antibodies when the antigen was targeted to the CD8α DC subset. On the other hand, antigen targeting to CD8α DC subset promoted specific antibody responses and proliferation, but no detectable pro-inflammatory CD4 T cell responses. Also, specific antibody responses after antigen targeting to CD8α or CD8α DCs were reduced in the absence of TLR9 or TLR5 signaling, while CD4 T cell proliferation was mainly affected after antigen targeting to CD8α DCs and in the absence of TLR9 signaling. These results extend our understanding of the modulation of specific immune responses induced by antigen targeting to DCs in the presence of different adjuvants. Such knowledge may be useful for the optimization of DC-based vaccines.

Adjuvants such as the aluminum compounds (alum) have been dominantly used in many vaccines due to their immunopotentiation and safety records since 1920s. However, how these mineral agents influence the immune response to vaccination remains elusive. Many hypotheses exist as to the mode of action of these adjuvants, such as depot formation, antigen (Ag) targeting, and the induction of inflammation. These hypotheses are based on many in vitro and few in vivo studies. Understanding how cells interact with adjuvants in vivo will be crucial to fully understanding the mechanisms of action of these adjuvants. Interestingly, how alum influences the target cell at both the cellular and molecular level, and the consequent innate and adaptive responses, will be critical in the rational design of effective vaccines against many diseases. Thus, in this review, mechanisms of action of alum have been discussed based on available in vitro vs in vivo evidences to date.

Vaccinations in medicine are commonly administered through the skin. Therefore, the vaccine is immunologically processed by antigen‐presenting cells of the skin. There is recent evidence that the clinically less often used intradermal route is effective; in cases even superior to the conventional subcutaneous or intramuscular route. Professional antigen‐presenting cells of the skin comprise epidermal Langerhans cells (CD207/langerin+), dermal langerin– and dermal langerin+ dendritic cells (DCs). In human skin, langerin– dermal DCs can be further subdivided on the basis of their reciprocal CD1a and CD14 expression. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Langerhans cells in human skin seem to be specialized for induction of cytotoxic T lymphocytes. Likewise, mouse Langerhans cells are capable of cross‐presentation and of protecting against experimental tumours. It is desirable to harness these properties for immunotherapy. A promising strategy to dramatically improve the outcome of vaccinations is ‘antigen targeting’. Thereby, the vaccine is delivered directly and selectively to defined types of skin DCs. Targeting is achieved by means of coupling antigen to antibodies that recognize cell surface receptors on DCs. This approach is being widely explored. Little is known, however, about the events that take place in the skin and the DCs subsets involved therein. This topic will be discussed in this article.