Dendritic cell subsets and implications for cancer immunotherapy.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

Vaccination with DC-SIGN-Targeting αGC Liposomes Leads to Tumor Control, Irrespective of Suboptimally Activated T-Cells.

Cancer vaccines have emerged as a potent strategy to improve cancer immunity, with or without the combination of checkpoint blockade. In our investigation, liposomal formulations containing synthetic long peptides and α-Galactosylceramide, along with a DC-SIGN-targeting ligand, Lewis Y (LeY), were studied for their anti-tumor potential. The formulated liposomes boosted with anti-CD40 adjuvant demonstrated robust invariant natural killer (iNKT), CD4+, and CD8+ T-cell activation in vivo. The incorporation of LeY facilitated the targeting of antigen-presenting cells expressing DC-SIGN in vitro and in vivo. Surprisingly, mice vaccinated with LeY-modified liposomes exhibited comparable tumor reduction and survival rates to those treated with untargeted counterparts despite a decrease in antigen-specific CD8+ T-cell responses. These results suggest that impaired induction of antigen-specific CD8+ T-cells via DC-SIGN targeting does not compromise anti-tumor potential, hinting at alternative immune activation routes beyond CD8+ T-cell activation.

Fusion of NY-ESO-1 epitope with heat shock protein 70 enhances its induced immune responses and antitumor activity against glioma in vitro.

Background: Glioma is the most common tumor originating in the brain and is difficult to cure. New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising cancer testis antigen (CTA) for tumor immunotherapy, and heat shock proteins (HSPs) can promote the antigen presentation of chaperoned peptides. This study investigates the therapeutic potential of HSP70 and NY-ESO-1 epitope fusion protein for glioma. Methods: Recombinant HSP70 protein was purified and fused to NY-ESO-1 epitope to generate HSP70/NY-ESO-1 p86-94. NY-ESO-1 expression was induced in U251 glioma cells via 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment. Dendritic cells (DCs) loaded with HSP70/NY-ESO-1 p86-94 or NY-ESO-1 protein stimulated NY-ESO-1-specific cytotoxic T lymphocytes (CTLs). The killing effect of NY-ESO-1 specific CTLs on U251 cells was detected by lactate dehydrogenase (LDH). Results: 5-Aza-CdR successfully induced NY-ESO-1 expression in U251 cells. NY-ESO-1-stimulated CTLs lysed more significantly with NY-ESO-1-positive U251 cells than with NY-ESO-1-negative cells. The immune response stimulated by a DC-based vaccine of HSP70/NY-ESO-1 p86-94 fusion protein was significantly enhanced compared with that induced by NY-ESO-1 alone. Conclusions: These findings indicate that the HSP70/NY-ESO-1 p86-94 may significantly enhance CTLs-mediated cytotoxicity and targeting ability against NY-ESO-1-expressing tumors in vitro. 5-Aza-CdR treatment with HSP70 binding to tumor antigen is a new strategy for immunotherapy of the tumors with poor CTA expression.

Lysosomal control of dendritic cell function.

Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded as stationary and digestive organelles, recent studies have increasingly appreciated the versatile roles of lysosomes in regulating key aspects of DC biology. Lysosomes actively control DC motility by linking calcium efflux to the actomyosin contraction, while enhanced DC lysosomal membrane permeability contributes to the inflammasome activation. Besides, lysosomes provide a platform for the transduction of innate immune signaling and the intricate host-pathogen interplay. Lysosomes and lysosome-associated structures are also critically engaged in antigen presentation and cross-presentation processes, which are pivotal for the induction of antigen-specific adaptive immune response. Through the current review, we emphasize that lysosome targeting strategies serve as vital DC-based immunotherapies in fighting against tumor, infectious diseases, and autoinflammatory disorders.

AXL receptor tyrosine kinase inhibition improves the anti-tumor effects of CD8+ T cells by inducing CD103+ dendritic cell-mediated T cell priming.

AXL is a member of TAM receptor family and has been highlighted as a potential target for cancer treatment. Accumulating evidence has uncovered the critical role of the AXL signaling pathway in tumor growth, metastasis, and resistance against anti-cancer drugs, as well as its association with cancer immune escape. However, the function of AXL as a manipulator of the immune system in the tumor microenvironment (TME) remains unclear. Therefore, in this study, we investigated the impact of AXL on immune cells in the TME of a syngeneic tumor model using AXL knockout (AXL-/-) mice. Compared to AXL wild-type (AXL+/+) mice, tumor growth was significantly suppressed in AXL-/- mice, and an induced population of tumor-infiltrated CD8+ T cells and CD103+ dendritic cells (DCs) was observed. The change of CD8+ T cells and CD103+ DCs was also confirmed in tumor-draining lymph nodes (TdLN). In addition, the clonal expansion of OVA-specific CD8+ T cells was dominant in AXL-/- mice. Finally, anti-PD-1 treatment evidenced synergistic anti-cancer effects in AXL-/- mice. Overall, our data indicate that AXL signaling may inhibit the clonal expansion of tumor-specific CD8+ T cells through the regulation of the migration of CD8+ T cells and DCs in TME. Thus, AXL may be a powerful molecular target to improve anti-cancer effects through single or combined therapy with immune checkpoint inhibitors (ICI).

L-Pampo™, a Novel TLR2/3 Agonist, Acts as a Potent Cancer Vaccine Adjuvant by Activating Draining Lymph Node Dendritic Cells.

TLR agonists have emerged as an efficient cancer vaccine adjuvant system that induces robust immune responses. L-pampo™, a proprietary vaccine adjuvant of TLR2 and TLR3 agonists, promotes strong humoral and cellular immune responses against infectious diseases. In this study, we demonstrate that vaccines formulated with L-pampo™ affect the recruitment and activation of dendritic cells (DCs) in draining lymph nodes (dLNs) and leading to antigen-specific T-cell responses and anti-tumor efficacy. We analyzed DC maturation and T-cell proliferation using flow cytometry and ELISA. We determined the effect of L-pampo™ on DCs in dLNs and antigen-specific T-cell responses using flow cytometric analysis and the ELISPOT assay. We employed murine tumor models and analyzed the anti-tumor effect of L-pampo™. We found that L-pampo™ directly enhanced the maturation and cytokine production of DCs and, consequently, T-cell proliferation. OVA or OVA peptide formulated with L-pampo™ promoted DC migration into dLNs and increased activation markers and specific DC subsets within dLNs. In addition, vaccines admixed with L-pampo™ promoted antigen-specific T-cell responses and anti-tumor efficacy. Moreover, the combination of L-pampo™ with an immune checkpoint inhibitor synergistically improved the anti-tumor effect. This study suggests that L-pampo™ can be a potent cancer vaccine adjuvant and a suitable candidate for combination immunotherapy.

Machine-learning and combined analysis of single-cell and bulk-RNA sequencing identified a DC gene signature to predict prognosis and immunotherapy response for patients with lung adenocarcinoma.

BACKGROUND: Innate immune effectors, dendritic cells (DCs), influence cancer prognosis and immunotherapy significantly. As such, dendritic cells are important in killing tumors and influencing tumor microenvironment, whereas their roles in lung adenocarcinoma (LUAD) are largely unknown. METHODS: In this study, 1658 LUAD patients from different cohorts were included. In addition, 724 cancer patients who received immunotherapy were also included. To identify DC marker genes in LUAD, we used single-cell RNAsequencing data for analysis and determined 83 genes as DC marker genes. Following that, integrative machine learning procedure was developed to construct a signature for DC marker genes. RESULTS: Using TCGA bulk-RNA sequencing data as the training set, we developed a signature consisting of seven genes and classified patients by their risk status. Another six independent cohorts demonstrated the signature' s prognostic power, and multivariate analysis demonstrated it was an independent prognostic factor. LUAD patients in the high-risk group displayed more advanced features, discriminatory immune-cell infiltrations and immunosuppressive states. Cell-cell communication analysis indicates that tumor cells with lower risk scores communicate more actively with the tumor microenvironment. Eight independent immunotherapy cohorts revealed that patients with low-risk had better immunotherapy responses. Drug sensitivity analysis indicated that targeted therapy agents exhibited greater sensitivity to low-risk patients, while chemotherapy agents displayed greater sensitivity to high-risk patients. In vitro experiments confirmed that CTSH is a novel protective factor for LUAD. CONCLUSIONS: An unique signature based on DC marker genes that is highly predictive of LUAD patients' prognosis and response to immunotherapy. CTSH is a new biomarker for LUAD.

Functional evaluation of rare OASL variants by analysis of SLE patient-derived iPSCs.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by genetic heterogeneity and an interferon (IFN) signature. The overall landscapes of the heritability of SLE remains unclear. OBJECTIVES: To identify and elucidate the biological functions of rare variants underlying SLE, we conducted analyses of patient-derived induced pluripotent stem cells (iPSCs) in combination with genetic analysis. METHODS: Two familial SLE patient- and two healthy donor (HD)-derived iPSCs were established. Type 1 IFN-secreting dendritic cells (DCs) were differentiated from iPSCs. Genetic analyses of SLE-iPSCs, and 117 SLE patients and 107 HDs in the ImmuNexUT database were performed independently. Genome editing of the variants on iPSCs was performed with the CRISPR/Cas9 system. RESULTS: Type 1 IFN secretion was significantly increased in DCs differentiated from SLE-iPSCs compared to HD-iPSCs. Genetic analyses revealed a rare variant in the 2'-5'-Oligoadenylate Synthetase Like (OASL) shared between SLE-iPSCs and another independent SLE patient, and significant accumulation of OASL variants among SLE patients (HD 0.93%, SLE 6.84%, OR 8.387) in the database. Genome editing of mutated OASL 202Q to wild-type 202 R or wild-type OASL 202 R to mutated 202Q resulted in reduced or enhanced Type 1 IFN secretion of DCs. Three other OASL variants (R60W, T261S and A447V) accumulated in SLE patients had also capacities to enhance Type 1 IFN secretion in response to dsRNA. CONCLUSIONS: We established a patient-derived iPSC-based strategy to investigate the linkage of genotype and phenotype in autoimmune diseases. Detailed case-based investigations using patient-derived iPSCs provide information to unveil the heritability of the pathogenesis of autoimmune diseases.

Diospyros malabarica fruit preparation mediates immunotherapeutic modulation and epigenetic regulation to evoke protection against non-small cell lung cancer (NSCLC).

ETHNOPHARMACOLOGICAL RELEVANCE: Diospyros malabarica is an ethnomedicinal plant with hypoglycaemic, anti-bacterial, and anti-cancer properties and it belongs to the Ebenaceae family which is well known for its medicinal uses since ancient times and application of its bark and unripened fruit has been significantly mentioned in Ayurvedic texts. The Diospyros malabarica species which is known as the Gaub in Hindi and Indian Persimmon in English is native to India, however, it is distributed throughout the tropics. AIM OF THE STUDY: As Diospyros malabarica fruit preparation (DFP) possesses medicinal values, the study aims to evaluate its role as natural, non-toxic, and cost-effective dendritic cells (DCs) maturing immunomodulatory agent and also as an epigenetic regulator to combat Non-small cell lung cancer (NSCLC) which is a type of lung cancer whose treatment options such as chemotherapy, radiation therapy, etc. are accompanied with some adverse side effects. Thus, immunotherapeutic strategies are in high demand to evoke tumor protective immunity against NSCLC without causing such side effects. MATERIALS AND METHODS: Peripheral Mononuclear Cells (PBMCs) derived monocytes of normal subjects and NSCLC patients were utilized to generate DCs matured with either LPS (LPSDC) or DFP (DFPDC). Mixed Lymphocyte Reaction (MLR) was carried out with the differentially matured DCs co-culturing T cells and cytotoxicity of lung cancer cells (A549) was measured through LDH release assay and cytokine profiling was carried out via ELISA respectively. PBMCs of normal subjects and NSCLC patients have transfected separately in vitrowith CRISPR-activation plasmid of p53 and CRISPR-Cas9 knockout plasmid of c-Myc to analyze epigenetic mechanism(s) in the presence and absence of DFP. RESULTS: Diospyros malabarica fruit preparation (DFP) treated DC upregulates the secretion of T helper (TH)1 cell specific cytokines (IFN-γ and IL-12) and signal transducer and activator of transcription molecules (STAT1 and STAT4). Furthermore, it also downregulates the secretion of TH2-specific cytokines (IL-4 and IL-10). Diospyros malabarica fruit preparation (DFP) enhances p53 expression by reducing methylation levels at the CpG island of the promoter region. Upon c-Myc knockout, epigenetic markers such as H3K4Me3, p53, H3K14Ac, BRCA1, and WASp were enhanced whereas H3K27Me3, JMJD3, and NOTCH1 were downregulated. CONCLUSION: Diospyros malabarica fruit preparation (DFP) not only increases the expression of type 1 specific cytokines but also augments tumor suppression modulating various epigenetic markers to evoke tumor protective immunity without any toxic activities.

The role of dendritic cells and their immunometabolism in rheumatoid arthritis.

Dendritic cells (DCs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA), a prototypic autoimmune disease characterized by chronic synovitis and joint destruction. Conventional dendritic cells (cDCs) with professional antigen-presenting functions are enriched in the RA synovium. In the synovium, the cDCs are activated and show both enhanced migratory capacities and T cell activation in comparison with peripheral blood cDCs. Plasmacytoid dendritic cells, another subtype of DCs capable of type I interferon production, are likely to be tolerogenic in RA. Monocyte-derived dendritic cells (moDCs), once called "inflammatory DCs", are localized in the RA synovium, and they induce T-helper 17 cell expansion and enhanced proinflammatory cytokine production. Recent studies revealed that synovial proinflammatory hypoxic environments are linked to metabolic reprogramming. Activation of cDCs in the RA synovium is accompanied by enhanced glycolysis and anabolism. In sharp contrast, promoting catabolism can induce tolerogenic DCs from monocytes. Herein, we review recent studies that address the roles of DCs and their immunometabolic features in RA. Immunometabolism of DCs could be a potential therapeutic target in RA.

Advances in dendritic cell vaccination therapy of cancer.

Traditionally, vaccines have helped eradication of several infectious diseases and also saved millions of lives in the human history. Those prophylactic vaccines have acted through inducing immune responses against a live attenuated, killed organism or antigenic subunits to protect the recipient against a real infection caused by the pathogenic microorganism. Nevertheless, development of anticancer vaccines as valuable targets in human health has faced challenges and requires further optimizations. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) that play essential roles in tumor immunotherapies through induction of CD8+ T cell immunity. Accordingly, various strategies have been tested to employ DCs as therapeutic vaccines for exploiting their activity against tumor cells. Application of whole tumor cells or purified/recombinant antigen peptides are the most common approaches for pulsing DCs, which then are injected back into the patients. Although some hopeful results are reported for a number of DC vaccines tested in animal and clinical trials of cancer patients, such approaches are still inefficient and require optimization. Failure of DC vaccination is postulated due to immunosuppressive tumor microenvironment (TME), overexpression of checkpoint proteins, suboptimal avidity of tumor-associated antigen (TAA)-specific T lymphocytes, and lack of appropriate adjuvants. In this review, we have an overview of the current experiments and trials evaluated the anticancer efficacy of DC vaccination as well as focusing on strategies to improve their potential including combination therapy with immune checkpoint inhibitors (ICIs).

The Potential of Dendritic-Cell-Based Vaccines to Modulate Type 3 Innate Lymphoid Cell Populations.

Dendritic cell (DC) vaccines are a type of immunotherapy that relies on the communication of DCs with other aspects of the immune system. DCs are potent antigen-presenting cells involved in the activation of innate immune responses and education of adaptive immunity, making them ideal targets for immunotherapies. Innate lymphoid cells (ILCs) are relatively newly identified in the field of immunology and have important roles in health and disease. The studies described here explored the communications between type 3 ILCs (ILC3s) and DCs using a murine model of DC-based vaccination. Local and systemic changes in ILC3 populations following the administration of a DC vaccine were observed, and upon challenge with B16F10 melanoma cells, changes in ILC3 populations in the lungs were observed. The interactions between DCs and ILC3s should be further explored to determine the potential that their communications could have in health, disease, and the development of immunotherapies.

Cellular immune states in SARS-CoV-2-induced disease.

The general immune state plays important roles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cells of the immune system are encountering rapid changes during the acute phase of SARS-CoV-2-induced disease. Reduced fraction of functional CD8+ T cells, disrupted cross-talking between CD8+ T cells with dendritic cells (DCs), and impaired immunological T-cell memory, along with the higher presence of hyperactive neutrophils, high expansion of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes, and attenuated cytotoxic capacity of natural killer (NK) cells, are all indicative of low efficient immunity against viral surge within the body. Immune state and responses from pro- or anti-inflammatory cells of the immune system to SARS-CoV-2 are discussed in this review. We also suggest some strategies to enhance the power of immune system against SARS-CoV-2-induced disease.

Capability of Human Dendritic Cells Pulsed with Autologous Induced Pluripotent Stem Cell Lysate to Induce Cytotoxic T Lymphocytes against HLA-A33-Matched Cancer Cells.

Irradiated murine induced-pluripotent stem cells (iPSCs) elicit the antitumor response in vivo. However, it is unclear whether human iPSCs would elicit antitumor effects. In the present study, we investigated the capability of human iPSC lysate (iPSL)-pulsed dendritic cells (DCs) (iPSL/DCs) to induce cancer-responsive cytotoxic T lymphocytes (CTLs) in vitro. iPSCs and DCs were induced from peripheral blood mononuclear cells isolated from a human leukocyte antigen (HLA)-A33 homozygous donor. The iPSL was pulsed with immature DCs, which were then stimulated to allow full maturation. The activated DCs were co-cultured with autologous CTLs and their responses to SW48 colorectal carcinoma cells (HLA-A32/A33), T47D breast cancer cells (HLA-A33/A33), and T98G glioblastoma cells (HLA-A02/A02) were tested with enzyme-linked immunospot (ELISPOT) assays. Comprehensive gene expression analysis revealed that the established iPSCs shared numerous tumor-associated antigens with the SW48 and T47D cells. Immunofluorescent analysis demonstrated that the fluorescent-labeled iPSL was captured by the immature DCs within 2 h. iPSL/DCs induced sufficient CTL numbers in 3 weeks for ELISPOT assays, which revealed that the induced CTLs responded to SW48 and T47D cells. Human iPSL/DCs induced cancer-responsive CTLs on HLA-A33-matched cancer cells in vitro and could be a promising universal cancer vaccine for treating and preventing cancer.

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy.

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

Mucosal delivery of nanovaccine strategy against COVID-19 and its variants.

Despite the global administration of approved COVID-19 vaccines (e.g., ChAdOx1 nCoV-19®, mRNA-1273®, BNT162b2®), the number of infections and fatalities continue to rise at an alarming rate because of the new variants such as Omicron and its subvariants. Including COVID-19 vaccines that are licensed for human use, most of the vaccines that are currently in clinical trials are administered via parenteral route. However, it has been proven that the parenteral vaccines do not induce localized immunity in the upper respiratory mucosal surface, and administration of the currently approved vaccines does not necessarily lead to sterilizing immunity. This further supports the necessity of a mucosal vaccine that blocks the main entrance route of COVID-19: nasal and oral mucosal surfaces. Understanding the mechanism of immune regulation of M cells and dendritic cells and targeting them can be another promising approach for the successful stimulation of the mucosal immune system. This paper reviews the basic mechanisms of the mucosal immunity elicited by mucosal vaccines and summarizes the practical aspects and challenges of nanotechnology-based vaccine platform development, as well as ligand hybrid nanoparticles as potentially effective target delivery agents for mucosal vaccines.

Transcriptional programming of immunoregulatory responses in human Langerhans cells.

Human epidermal Langerhans cells (LCs) maintain immune homeostasis in the skin. To examine transcriptional programming of human primary LCs during homeostasis, we performed scRNA-seq analysis of LCs before and after migration from the epidermis, coupled with functional assessment of their regulatory T cell priming capabilities. The analysis revealed that steady-state LCs exist in a continuum of maturation states and upregulate antigen presentation genes along with an immunoregulatory module including the genes IDO1, LGALS1, LAMTOR1, IL4I, upon their migration. The migration-induced transition in genomic state is accompanied by the ability of LCs to more efficiently prime regulatory T cell responses in co-culture assays. Computational analyses of the scRNAseq datasets using SCENIC and Partial Information Decomposition in Context identified a set of migration-induced transcription factors including IRF4, KLF6 and RelB as key nodes within a immunoregulatory gene regulatory network. These findings support a model in which efficient priming of immunoregulatory responses by LCs is dependent on coordinated upregulation of a migration-coupled maturation program with a immunoregulation-promoting genomic module.

Activated Natural Killer Cells-Dependent Dendritic Cells Recruitment and Maturation by Responsive Nanogels for Targeting Pancreatic Cancer Immunotherapy.

Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as CC motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8+ T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.

Targeting thymidine phosphorylase alleviates resistance to dendritic cell immunotherapy in colorectal cancer and promotes antitumor immunity.

T-cell exhaustion plays a pivotal role in the resistance of microsatellite-stable colorectal cancer (CRC) to immunotherapy. Identifying and targeting T-cell exhaustion-activating mechanisms is a promising strategy to augment the effects of immunotherapy. Here, we found that thymidine phosphorylase (TYMP) plays a decisive role in inducing systemic T-cell exhaustion and abrogating the efficacy of dendritic cell (DC) therapy in a CRC model. Targeting TYMP with tipiracil hydrochloride (TPI) induces immunological cell death (ICD). The combined effects of TPI and imiquimod-activated DCs turn CT26 tumors into immunologically 'hot' tumors by inducing ICD in vivo. High-dimensional cytometry analysis revealed T-cell and IFN-γ dependency on the therapeutic outcome. In addition, chemoimmunotherapy converts intratumoral Treg cells into Th1 effector cells and eliminates tumor-associated macrophages, resulting in higher cytotoxic T lymphocyte infiltration and activation. This effect is also associated with the downregulation of PD-L1 expression in tumors, leading to the prevention of T-cell exhaustion. Thus, cooperative and cognitive interactions between dendritic cells and immunogenic cell death induced by therapy with TPI promote the immune response and tumoricidal activities against microsatellite stable colorectal cancer. Our results support TYMP targeting to improve the effects of DC immunotherapy and outcomes in CRC.

Dendritic Cells and Macrophages in the Pathogenesis of Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by scaly indurated erythema. This disease impairs patients' quality of life enormously. Pathological findings demonstrate proliferation and abnormal differentiation of keratinocytes and massive infiltration of inflammatory immune cells. The pathogenesis of psoriasis is complicated. Among immune cells, dendritic cells play a pivotal role in the development of psoriasis in both the initiation and the maintenance phases. In addition, it has been indicated that macrophages contribute to the pathogenesis of psoriasis especially in the initiation phase, although studies on macrophages are limited. In this article, we review the roles of dendritic cells and macrophages in the pathogenesis of psoriasis.