Dendritic Cells In Tumor Microenvironment Research Articles

Dysfunction of dendritic cells in tumor microenvironment and immunotherapy.

Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.

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).

Dendritic cell vaccines improve the glioma microenvironment: Influence, challenges, and future directions.

Gliomas, especially the glioblastomas, are one of the most aggressive intracranial tumors with poor prognosis. This might be explained by the heterogeneity of tumor cells and the inhibitory immunological microenvironment. Dendritic cells (DCs), as the most potent in vivo functional antigen-presenting cells, link innate immunity with adaptive immunity. However, their function is suppressed in gliomas. Therefore, overcoming the dysfunction of DCs in the TME might be critical to treat gliomas. In this paper we proposed the specificity of the glioma microenvironment, analyzed the pathways leading to the dysfunction of DCs in tumor microenvironment of patients with glioma, summarized influence of DC-based immunotherapy on the tumor microenvironment and proposed new development directions and possible challenges of DC vaccines. DC vaccines can improve the immunosuppressive microenvironment of glioma patients. It will bring good treatment prospects to patients. We also proposed new development directions and possible challenges of DC vaccines, thus providing an integrated understanding of efficacy on DC vaccines for glioma treatment.

Decreased CD11c-positive dendritic cells in the tumor microenvironment predict double-hit/triple-hit genotype and survival in diffuse large B-cell lymphoma.

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of non‐Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double‐hit [DH] lymphoma), or fusions involving all three genes (triple‐hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin‐fixed paraffin‐embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well‐performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future.

Metabolism of Dendritic Cells in Tumor Microenvironment: For Immunotherapy.

Dendritic cells (DCs) are a type of an antigen-presenting cell which undertake a job on capturing antigens coming from pathogens or tumors and presenting to T cells for immune response. The metabolism of DCs controls its development, polarization, and maturation processes and provides energy support for its functions. However, the immune activity of DCs in tumor microenvironment (TME) is inhibited generally. Abnormal metabolism of tumor cells causes metabolic changes in TME, such as hyperglycolysis, lactate and lipid accumulation, acidification, tryptophan deprivation, which limit the function of DCs and lead to the occurrence of tumor immune escape. Combined metabolic regulation with immunotherapy can strengthen the ability of antigen-presentation and T cell activation of DCs, improve the existing anti-tumor therapy, and overcome the defects of DC-related therapies in the current stage, which has great potential in oncology therapy. Therefore, we reviewed the glucose, lipid, and amino acid metabolism of DCs, as well as the metabolic changes after being affected by TME. Together with the potential metabolic targets of DCs, possible anti-tumor therapeutic pathways were summarized.

Immune escape mechanisms and immunotherapy of urothelial bladder cancer

Urothelial bladder cancer (UBC) is a common malignant tumor of the urogenital system with a high rate of recurrence. Due to the sophisticated and largely unexplored mechanisms of tumorigenesis of UBC, the classical therapeutic approaches including transurethral resection and radical cystectomy combined with chemotherapy have remained unchanged for decades. However, with increasingly in-depth understanding of the microenvironment and the composition of tumor-infiltrating lymphocytes of UBC, novel immunotherapeutic strategies have been developed. Bacillus Calmette-Guerin (BCG) therapy, immune checkpoint blockades, adoptive T cell immunotherapy, dendritic cell (DC) vaccines, etc., have all been intensively investigated as immunotherapies for UBC. This review will discuss the recent progress in immune escape mechanisms and immunotherapy of UBC.Based on a comprehensive search of the PubMed and ClinicalTrials.gov database, this review included the literature reporting the immune escape mechanisms of UBC and clinical trials assessing the effect of immunotherapeutic strategies on tumor or immune cells in UBC patients published in English between 1999 and 2020.Immune surveillance, immune balance, and immune escape are the three major processes that occur during UBC tumorigenesis. First, the role of immunosuppressive cells, immunosuppressive molecules, immunosuppressive signaling molecules, and DCs in tumor microenvironment is introduced elaborately in the immune escape mechanisms of UBC section. In addition, recent progress of immunotherapies including BCG, checkpoint inhibitors, cytokines, adoptive T cell immunotherapy, DCs, and macrophages on UBC patients are summarized in detail. Finally, the need to explore the mechanisms, molecular characteristics and immune landscape during UBC tumorigenesis and development of novel and robust immunotherapies for UBC are also proposed and discussed.At present, BCG and immune checkpoint blockades have been approved by the US Food and Drug Administration for the treatment of UBC patients and have achieved encouraging therapeutic results, expanding the traditional chemotherapy and surgery-based treatment for UBC.Immunotherapy has achieved desirable results in the treatment of UBC, which not only improve the overall survival but also reduce the recurrence rate and the occurrence of treatment-related adverse events of UBC patients. In addition, the indicators to predict the effectiveness and novel therapy strategies, such as combination regimen of checkpoint inhibitor with checkpoint inhibitor or chemotherapy, should be further studied.

Tyrosine kinase inhibitors modulate dendritic cell activity via confining c-Kit signaling and tryptophan metabolism

Dendritic cell (DC)-based vaccine has been established in tumor immunotherapy. Importantly, the efficiency of anti-tumor T-cells in draining lymph nodes is dependent on the status of DCs surrounding in tumors. It has been shown that Indoleamine 2,3-dioxygenase (IDO) plays a key role to induce tolerogenic DCs in tumor microenvironment, and tyrosine kinase inhibitors (TKIs) can suppress the function of IDO in DCs. However, the stimulatory effect of TKI-modified DCs on T cells remains unclear. In this report, we found that one type of TKI-dasatinib can modify DCs to increasing the activation of allogenic T cells. These TKI-modified DCs delayed the onset of B16 melanoma progression in mice. In mechanistic studies, TKIs did not increase the maturation but reduce the expression and phosphorylation levels of IDO and IDO mediated tryptophan metabolism in DCs. In addition, the suppressive effect of TKIs on tryptophan metabolism may be caused by blocking c-Kit pathway in DCs. Furthermore, the increased phosphorylation of general control nonderepressible (GCN2) and decreased expression of aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (ARNT) were observed in the T cells activated by TKI-modified DCs, suggesting the enhancement of effector function of T cells. These results indicate that TKI could be used to modulate DC immunogenic activity and may potentially be applied in DC-based cancer immunotherapy.

Dendritic cells in tumor microenvironment promoted the neuropathic pain via paracrine inflammatory and growth factors

ABSTRACT Neuropathic pain associated with cancers was caused by tumor itself or tumor therapy, which was aggravated by sensitizing nociceptor sensory neurons. The tumor microenvironment contributed to tumorigenesis, tumor progress, tumor metastasis, tumor immune resistance, tumor chemotherapy, and tumor immunotherapy. In the current study, we explored the contributions of the infiltrated dendritic cells insulted by Wnt1 in tumor microenvironment to neuropathic pain associated with cancers. The different transcriptome of infiltrated dendritic cells from lung adenocarcinoma and from juxtatumor indicated that thousands of genes were up-regulated by the tumor microenvironment, some of which were enriched in pain pathway. The paracrine factors such as TNF, WNT10A, PDGFA, and NRG1 were also elevated in tumor-infiltrating dendritic cells. The receptors of paracrine factors were highly expressed on dorsal root ganglia (DRG), and not altered in pain conditions. Single-cell RNA-seq data unveiled that TNFSF1 was expressed in neurons, microglial cells, and endothelial cells. PDGFRA was only expressed in microglial cells. ERBB3 was only expressed in neurons. FZD1 and 3 were extensively expressed in various cells. The components composed of signaling pathways associated with the above paracrine factors participated in pain networks. The transcription factors activated by paracrine factor signaling regulated the expression of genes associated with pain. TNF, WNT10A, and PDGFA were extensively expressed in multiple cancers, but their expression in patients did not distribute normally. These data indicated that infiltrated dendritic cells in tumor microenvironment promoted neuropathic pain by sensitizing nociceptor sensory neurons via paracrine factors. Blockage of paracrine factor signaling might alleviate cancer pain.

The dendritic cell tool for oral cancer treatment.

The link between oncology and immunology has a long history, and its development is forced by the necessity to develop innovative and highly efficient modalities for the immunological destruction of malignant cells. The success of cancer immunotherapy depends on two major factors: adequate tumor-specific antigens and a vehicle capable of inducing a tumor-specific immune response by effective delivery of these antigens. Dendritic cells (DCs) are the most powerful antigen-presenting cells, because of their unique characteristics, and these cells are actively used in cancer immunotherapy. DCs form a critical interface between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T-cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T-cell differentiation. They are sentinel of immune system, as they are deployed through the body and monitor their surroundings for antigens and danger signals derived from pathogens or tissue damage. These cells (DCs) with their potent antigen-presenting ability are considered as critical factor in antitumor immunity. In recent years, the existence of immunosuppressive regulatory DCs in tumor microenvironment is well described. Monocytic myeloid-derived suppressor cells can contribute to the pool of tumor-associated DCs by differentiating to inflammatory DCs, which appear to have specific phenotype and are critical components of antitumor response. There is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs and the generation of DC-based vaccines. Here, we highlight the role of DCs along with other DC subsets in the regulation of immune responses in cancer treatment.

IL-6/STAT3 signaling impaired induction of cancer-antigen specific T cells via down-regulation of dendritic cells in tumor microenvironment.

590 Background: Immunosuppression in tumor microenvironments is a critical issue for cancer immunotherapy. Recently, the effectiveness of immuno-check point therapy has been reported on various types of solid tumors. But, the effectiveness in colorectal cancer was poor compared to other cancers, such as melanoma and renal cell carcinoma. Correct regulation of dendritic cell (DC) function in tumors is important for inducing anti-tumor immunity. We have been demonstrated that IL-6 inhibits antigen presentation by DCs through STAT3 activation in tumor-bearing mice. In this study, we focused on the role of the IL-6/STAT3 signaling cascade in human DCs. Methods: Both IL-6 and pSTAT3 expressions in tumor sites of colorectal cancers was verified by immunohistostaining. CD11b+CD11c+DCs in cancer tissues and PBMCs were isolated by fluorescence-activated cell sorting system and investigated about the surface molecules such as HLA-DR, T cell stimulating ability, and effector gene expression levels. Moreover, we investigated influence of IL-6/STAT3 signaling in human DCs in vitro. Results: The results of IHC revealed that IL-6 was preferentially produced by cancer-associated fibroblasts and immune cells in the tissues of colorectal cancers. In addition, it was confirmed that STAT3 was activated in tumor-infiltrating immune cells. Tumor infiltrating CD11b+CD11c+ DCs highly induced IL-6 gene, down-regulated surface expression of HLA-DR, and attenuated T cell stimulating ability. In vitro experiments showed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR. COX2, cathepsin L (CTSL), and arginase activity were are involved in the IL-6-mediated down-regulation of surface expression levels of HLA-DR expression levels on DCs. Gene expressions of CTSL, ARG1 as well as IL6 in tumor infiltrating CD11b+CD11c+DCs were much higher than those of PBMCs. Conclusions: IL-6-mediated STAT3 activation inhibits functional maturation of DCs, causing suppression of anti-tumor immunity in colorectal cancer. Therefore, inhibition of the IL-6/STAT3 signaling pathway could be a promising strategy for improving immunotherapies for colorectal cancer patients.

Non-small Cell Lung Cancer Induces an Immunosuppressive Phenotype of Dendritic Cells in Tumor Microenvironment by Upregulating B7-H3

Tumors may shift the phenotype and function of dendritic cells (DC) toward the induction of tolerance. In the status of full maturity, DC express a multitude of T cell costimulatory molecules enabling them to induce immune reactions, whereas nonactivated resident DC lack these T cell stimulating capacities. Therefore, we investigated the changes in DC phenotype and expression of B7-H molecules induced by non-small cell lung cancer (NSCLC). The expression of T cell coinhibitory B7 molecules (B7-DC, B7-1, B7-2, B7-H1, B7-H3) on DC isolated from malignant and nonmalignant lung and lymph node tissue from patients attending curative surgery for NSCLC (n = 12) was analyzed. T cell stimulatory functions of DC isolated from malignant and nonmalignant lung and lymph node tissue samples were measured by allogeneic mixed lymphocyte reactions. Furthermore, the secretion of IL-10 and IL-12p40 by DC was analyzed (enzyme-linked immunosorbent assay). : B7-H3 was significantly upregulated in tumor-residing DC, whereas the expression of other B7 molecules, such as B7-DC, B7-1, B7-2, B7-H1, remained unchanged. Significantly reduced levels of T cell proliferation in mixed lymphocyte reactions with tumor-derived DC were recorded. Moreover, elevated concentrations of IL-10 were measured in tumor-derived DC, whereas IL-12 levels were reduced. Our data indicate that (1) DC derived from NSCLC are immunosuppressive, and (2) under tumor conditions the coinhibitory molecule B7-H3 plays a crucial role in mediating the T cell suppressive effects of DC.

Combined mobilization and stimulation of tumor‐infiltrating dendritic cells and natural killer cells with Flt3 ligand and IL‐18 in vivo induces systemic antitumor immunity

It was hypothesized that if dendritic cells (DC) could be efficiently manipulated in vivo, this might enable functional maturation and retention of their potent functions and might represent a more promising approach in DC immunotherapy. The present study focused on the modulation of DC in tumor microenvironment using Fms-like thyrosine kinase 3 ligand (Flt3L) combined with interferon-gamma-inducing factor (IL-18). Tumor-inoculated mice were treated with in vivo electroporation (IVE) of expression plasmids carrying complementary DNA of Flt3L. As a combination therapy, mice in the other group were treated with intra-tumoral injection of adenoviral vector carrying IL-18 gene (Ad.IL-18). Significant antitumor effect was observed in mice treated with Ad.IL-18 alone when compared with that of control (P < 0.01). Complete eradication was observed more frequently (100%versus 33%: P < 0.05) in the mice treated with Flt3L and Ad.IL-18 when compared with the mice treated with Ad.IL-18 alone. In un-injected distant tumor, significant antitumor responses were observed only in the mice treated with combination therapy. Lymphoid cells in lymph nodes of mice treated with combination therapy showed significant cytolytic activity against inoculated tumor cells and YAC-1 cells when compared with the lymphoid cells in other groups. In the tumor microenvironment, combination therapy resulted in the recruitment of mobilized DC into the tumor bed, although Flt3L-IVE alone had an effect in the peri-tumoral area. Tumor-infiltrating DC in mice treated with combination therapy showed higher CD86 expression and more potent allogeneic T-cell stimulatory capacity. These results may suggest that local expression of IL-18 combined with in vivo DC mobilization with Flt3L is clinically applicable as a new strategy of DC immunotherapy.

Effects of Lycium barbarum polysaccharide on tumor microenvironment T-lymphocyte subsets and dendritic cells in H22-bearing mice

To study the effects of Lycium barbarum polysaccharide (LBP) on tumor microenvironment T-lymphocyte subsets and dendritic cells in H22-bearing mice and the mechanisms for intervention of tumor immune escape by LBP. H22-bearing mice were given LBP orally for two weeks. T-lymphocyte subsets and the phenotypes of dendritic cells in tumor-infiltrating lymphocytes (TIL) were detected by flow cytometry (FCM). LBP could significantly increase the numbers of CD4(+) and CD8(+) T cells in TIL as compared with those in model control group (P<0.05). In model control group, the number of dendritic cells in tumor microenvironment decreased markedly, while in LBP-treated group, the increased number of dendritic cells and B7-1 expression were observed, but there were no significant differences between these two groups. LBP has anti-tumor effect probably by increasing the numbers of CD4(+) and CD8(+) T cells in TIL to relieve the immunosuppression and enhance the anti-tumor function of the immune system. But whether LBP can recover the phenocyte and function of dendritic cells in H22-bearing mice should be further studied.