Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8+/CD4+ T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications. 

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2022.2096363?needAccess=true

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

Background: Excessive immune activation leads to secondary injury and impedes injured brain recovery after ischemic stroke. However, few effective methods are currently used for equilibrating immune balance. CD3 + NK1.1 - TCR β + CD4 – CD8 – double-negative T (DNT) cells which do not express NK cell surface markers are unique regulatory cells that maintain homeostasis in several immune-related diseases. However, the therapeutic potential and regulatory mechanism of DNT cells in ischemic stroke are still unknown. Methods: Mouse ischemic stroke is induced by occlusion of the distal branches of the middle cerebral artery (dMCAO). DNT cells were adoptively transferred intravenously into ischemic stroke mice. Neural recovery was evaluated by TTC staining and behavioral analysis. Using immunofluorescence, flow cytometry, and RNA sequencing, the immune regulatory function of DNT cells was investigated at different time points post ischemic stroke. Results: Adoptive transfer of DNT cells significantly reduces infarct volume and improves sensorimotor function after ischemic stroke. DNT cells suppress peripheral Trem1 + myeloid cell differentiation during the acute phase. Furthermore, they infiltrate the ischemic tissue via CCR5 and equilibrate the local immune balance during the subacute phase. During the chronic phase, DNT cells enhance Treg cell recruitment through CCL5, eventually developing an immune homeostatic milieu for neuronal recovery. Conclusions: DNT cell treatment renders the comprehensive anti-inflammatory roles in specific phases of ischemic stroke. Our study suggests that the adoptive transfer of regulatory DNT cells may be a potential cell-based therapy for ischemic stroke.

Theranostics: MRI-Visualized, Dual-Targeting, Combined Tumor Therapy Using Magnetic Graphene-Based Mesoporous Silica (Small 1/2014)

Background Ovarian cancer (OC) is one of the most common and most malignant gynecological malignancies in gynecology. On the other hand, dysregulation of copper metabolism (CM) is closely associated with tumourigenesis and progression. Here, we investigated the impact of genes associated with copper metabolism (CMRGs) on the prognosis of OC, discovered various CM clusters, and built a risk model to evaluate patient prognosis, immunological features, and therapy response. Methods 15 CMRGs affecting the prognosis of OC patients were identified in The Cancer Genome Atlas (TCGA). Consensus Clustering was used to identify two CM clusters. lasso-cox methods were used to establish the copper metabolism-related gene prognostic signature (CMRGPS) based on differentially expressed genes in the two clusters. The GSE63885 cohort was used as an external validation cohort. Expression of CM risk score-associated genes was verified by single-cell sequencing and quantitative real-time PCR (qRT-PCR). Nomograms were used to visually depict the clinical value of CMRGPS. Differences in clinical traits, immune cell infiltration, and tumor mutational load (TMB) between risk groups were also extensively examined. Tumour Immune Dysfunction and Rejection (TIDE) and Immune Phenotype Score (IPS) were used to validate whether CMRGPS could predict response to immunotherapy in OC patients. Results In the TCGA and GSE63885 cohorts, we identified two CM clusters that differed significantly in terms of overall survival (OS) and tumor microenvironment. We then created a CMRGPS containing 11 genes to predict overall survival and confirmed its reliable predictive power for OC patients. The expression of CM risk score-related genes was validated by qRT-PCR. Patients with OC were divided into low-risk (LR) and high-risk (HR) groups based on the median CM risk score, with better survival in the LR group. The 5-year AUC value reached 0.74. Enrichment analysis showed that the LR group was associated with tumor immune-related pathways. The results of TIDE and IPS showed a better response to immunotherapy in the LR group. Conclusion Our study, therefore, provides a valuable tool to further guide clinical management and tailor the treatment of patients with OC, offering new insights into individualized treatment.

/pdf/identification-of-copper-metabolism-related-subtypes-and-2ne4pisc.pdf

Identification of copper metabolism-related subtypes and establishment of the prognostic model in ovarian cancer

ABSTRACT Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8+/CD4+ T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

Bifidobacterium is a widely distributed commensal bacterial genus that displays beneficial pro-homeostatic and anti-inflammatory immunomodulatory properties. Depletion or absence of Bifidobacterium in humans and model organisms is associated with autoimmune responses and impaired immune homeostasis. At the cellular level, Bifidobacterium upregulates suppressive regulatory T cells, maintains intestinal barrier function, modulates dendritic cell and macrophage activity, and dampens intestinal Th2 and Th17 programs. While there has been a large volume of literature characterizing the probiotic properties of various Bifidobacterial species, the likely multifactorial mechanisms underlying these effects remain elusive, in particular, its immune tolerogenic effect. However, recent work has shed light on Bifidobacterium surface structural polysaccharide and protein elements, as well as its metabolic products, as commensal mediators of immune homeostasis. This review aims to discuss several mechanisms Bifidobacterium utilizes for immune modulation as well as their indirect impact on the regulation of gut microbiome structure and function, from structural molecules to produced metabolites. These mechanisms are pertinent to an increasingly networked understanding of immune tolerance and homeostasis in health and disease.

Bifidobacterium mechanisms of immune modulation and tolerance.

Recent advances in immunotherapy, as a part of the multidisciplinary therapy, has gradually gained more attention. However, only a small proportion of patients who sensitive to the therapy could gain benefits. An increasing number of studies indicate that intestinal microbiota could enhance the efficiency of cancer immunotherapy. As one of the main probiotics, Bifidobacterium plays an important role in immune regulation, which has been proved by animal research and human clinical study. But the detailed mechanism was not clearly elucidated. Here we found oral administration of Bifidobacterium breve (B. breve) lw01 could significantly inhibit tumor growth and up-regulate tumor cell apoptosis, which relied on the recruitment of tumor-infiltrating lymphocytes and dendritic cells (DCs) in tumor microenvironment, but not Lactobacillus rhamnosus (L. rhamnosus) CGMCC 1.3724 or Escherichia coli (E. coli) MG1655. In the in situ ligated intestine loop model, B. breve's stimulation triggered the upregulated expression of DC-related chemokine CCL20 and recruited more DCs in the intestinal villi. Further study revealed the enhancement of interleukin 12 (IL-12) secretion derived from DCs is essential to B. breve's antitumor effect, which was counteracted by the treatment of neutralizing antibody for IL-12. Meanwhile, the modulation of intestinal microbiota caused by exogenous B. breve might enhance its antitumor effect. This study provides a simple and easy way to promote antitumor immunity via B. breve.

Oral administration of Bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived interleukin 12.

The tumor microenvironment (TME) has a crucial role in tumor development, progression, and treatment response. Yet, the exact interaction between cancer biology and the TME is not fully understood. The following study analyzed the correlation between immune/stromal/estimate scores and survival prognosis in head and neck squamous cell carcinoma (HNSC) using a bioinformatic method. As a result, a predictive biomarker, UDP-glucose-specific G(i) protein-coupled P2Y receptor (P2RY14), was discovered. The potential role of P2RY14-driven signaling pathways in the immune-remodeling of TME was then investigated. Briefly, low immune scores were associated with unfavorable prognosis and clinical-stage, larger tumor size, and the down-regulation of P2RY14 in HNSC patients. In addition, the survival analysis showed that HNSC patients with high expression had longer survival than patients with low expression from both TCGA databases and our own patients. We further discovered that P2RY14 is involved in the immune activity in the TME of HNSC; a downregulation of P2RY14 resulted in being an indicator for the conversion of TME status (from immune-dominant to metabolic-dominant status). The intersection analysis of genes co-expressed with P2RY14 indicated that the T-cell receptor signaling pathway and PD-L1 expression and PD-1 checkpoint pathway were candidate signaling pathways driven by the P2RY14 gene in HNSC. Further investigation of immune-associated signaling pathways regulated by P2RY14 may help HNSC patients gain higher immunotherapy benefits.

/pdf/p2ry14-is-a-potential-biomarker-of-tumor-microenvironment-4wdytej51d.pdf

P2RY14 Is a Potential Biomarker of Tumor Microenvironment Immunomodulation and Favorable Prognosis in Patients With Head and Neck Cancer

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Oral administration of Bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived interleukin 12.

P2RY14 Is a Potential Biomarker of Tumor Microenvironment Immunomodulation and Favorable Prognosis in Patients With Head and Neck Cancer