Jingtao Chen

Targeting immune checkpoints in malignant glioma

Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma.

Recent advances in the role of toll-like receptors and TLR agonists in immunotherapy for human glioma.

ABSTRACTGliomas are extremely aggressive brain tumors with a very poor prognosis. One of the more promising strategies for the treatment of human gliomas is targeted immunotherapy where antigens that are unique to the tumors are exploited to generate vaccines. The approach, however, is complicated by the fact that human gliomas escape immune surveillance by creating an immune suppressed microenvironment. In order to oppose the glioma imposed immune suppression, molecules and pathways involved in immune cell maturation, expansion, and migration are under intensive clinical investigation as adjuvant therapy. Toll-like receptors (TLRs) mediate many of these functions in immune cell types, and TLR agonists, thus, are currently primary candidate molecules to be used as important adjuvants in a variety of cancers. In animal models for glioma, TLR agonists have exhibited antitumor properties by facilitating antigen presentation and stimulating innate and adaptive immunity. In clinical trials, several TLR agonists have achieved survival benefit, and many more trials are recruiting or ongoing. However, a second complicating factor is that TLRs are also expressed on cancer cells where they can participate instead in a variety of tumor promoting activities including cell growth, proliferation, invasion, migration, and even stem cell maintenance. TLR agonists can, therefore, possibly play dual roles in tumor biology. Here, how TLRs and TLR agonists function in glioma biology and in anti-glioma therapies is summarized in an effort to provide a current picture of the sophisticated relationship of glioma with the immune system and the implications for immunotherapy.

1,25‐dihydroxyvitamin D3‐induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells

Dendritic cells (DCs), a bridge for innate and adaptive immune responses, play a key role in the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Administration of tolerogenic DCs has been used as an immunotherapy in autoimmune diseases. Deficiency of vitamin D is an environmental risk factor of MS. In this study, we induced tolerogenic DCs by 1,25‐dihydroxyvitamin D3 and transferred the tolerogenic DCs (VD3‐DCs) into EAE mice by adoptive transfer. We found that VD3‐DCs inhibited the infiltrations of T helper type 1 (Th1) and Th17 cells into spinal cord and increased the proportions of regulatory T cells (CD4+ CD25+ Foxp3+), CD4+ IL‐10+ T cells and regulatory B cells (CD19+ CD5+ CD1d+) in peripheral immune organs, which resulted in attenuated EAE. However, the proportions of T helper type 1 (Th1) and Th17 cells in spleen and lymph nodes and the levels of pro‐inflammatory cytokines and IgG in serum also increased after transfer of VD3‐DCs. We conclude that transfer of VD3‐DCs suppressed EAE by increasing proportions of regulatory T cells, CD4+ IL‐10+ T cells and regulatory B cells in spleen and reducing infiltration of Th1 and Th17 cells into spinal cord, which suggests a possible immunotherapy method using VD3‐DCs in MS.

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo

Plasmacytoid dendritic cells (pDCs) are a unique subset of naturally occurring dendritic cells, which triggers the production of large amounts of type I interferons (IFNs) after viral infections through Toll-like receptor (TLR) 7 and TLR9. Recent studies have demonstrated that the activation of pDCs kills melanoma cells. However, the role of activated pDCs in breast cancer remains to be determined. In the present study, we generated mouse models of breast cancer and demonstrated that activated pDCs can directly kill breast tumor cells through TRAIL and Granzyme B. Furthermore, we established that pDCs initiate the sequential activation of NK cells and CD8+ T cells, and ultimately inhibit breast tumor growth. Understanding the role of activated pDCs in breast cancer may help to develop new strategies for manipulating the function of pDCs and induce anti-tumor immunity in breast cancer.

Disease-Associated Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs), also called natural interferon (IFN)-producing cells, represent a specialized cell type within the innate immune system. pDCs are specialized in sensing viral RNA and DNA by toll-like receptor-7 and -9 and have the ability to rapidly produce massive amounts of type 1 IFNs upon viral encounter. After producing type 1 IFNs, pDCs differentiate into professional antigen-presenting cells, which are capable of stimulating T cells of the adaptive immune system. Chronic activation of human pDCs by self-DNA or mitochondrial DNA contributes to the pathogenesis of systemic lupus erythematosis and IFN-related autoimmune diseases. Under steady-state conditions, pDCs play an important role in immune tolerance. In many types of human cancers, recruitment of pDCs to the tumor microenvironment contributes to the induction of immune tolerance. Here, we provide a systemic review of recent progress in studies on the role of pDCs in human diseases, including cancers and autoimmune/inflammatory diseases.

Human cancer cells respond to cytosolic nucleic acids via enhanced production of interferon-β and apoptosis

The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses. Recently, it was reported that human cancer cells also expressed PRRs, and responded to cytosolic nucleic acids via the production of type I interferon and apoptosis in susceptible cells. However, the definite nucleic acids senses in different cancer cells remains unclear. In this study, we investigated the effects of nucleic acids in eight types of cancer cells, including pancreatic cancer, glioma, breast cancer, lung cancer, hepatoma, gastric cancer, colorectal cancer, and cervical cancer. We found that IFN-β secretion was increased after poly(I:C) and poly(dA:dT) stimulation. In order to understand the mechanism, we established the role of TLR3 and RIG-I/MDA-5 signaling in pancreatic cancer cell line PANC-1. poly(I:C) and poly(dA:dT) upregulated the expression of PKR, TLR3, RIG-I, MDA5 and LGP2. Knockdown experiments confirmed PKR, TLR3, TRIF, RIG-I, LGP2, and IPS-1 involved in response to cytosolic poly(I:C) and poly(dA:dT). In addition, poly(I:C) and poly(dA:dT) induced apoptosis via caspase-8 and caspase-9 in pancreatic cancer cells. In summary, cytosolic poly(I:C) and poly(dA:dT) induce IFN-β secretion via TLR3-TRIF and RIG-I/LGP2-IPS-1 signaling pathway and apoptosis in a caspase-dependent manner at cancer cells. This study may provide a novel way for drug and vaccine design on cancer immunotherapy.

MicroRNAs: Pleiotropic regulators in the tumor microenvironment

MicroRNAs (miRNAs) are small non-coding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs). They are ~22 nucleotides long and control both physiological and pathological processes. Altered expression of miRNAs is often associated with human diseases. Thus, miRNAs have become important therapeutic targets, and some clinical trials investigating the effect of miRNA-based therapeutics in different types of diseases have already been conducted. The tumor microenvironment (TME) comprises cells such as infiltrated immune cells, cancer-associated endothelial cells (CAEs) and cancer-associated fibroblasts (CAFs), and all the components participate in the complicated crosstalk with tumor cells to affect tumor progression. Altered miRNAs expression in both these stromal and tumor cells could drive tumorigenesis. Thus, in this review, we discuss how aberrantly expressed miRNAs influence tumor progression; summarize the crosstalk between infiltrated immune cells, CAEs, CAFs, and tumor cells through miRNAs, and clarify the important roles of miRNAs in the tumor microenvironment, which may facilitate the clinical application of miRNA-based therapies.

Decitabine Inhibits Gamma Delta T Cell Cytotoxicity by Promoting KIR2DL2/3 Expression

Gamma delta (γδ) T cells, which possess potent cytotoxicity against a wide range of cancer cells, have become a potential avenue for adoptive immunotherapy. Decitabine (DAC) has been reported to enhance the immunogenicity of tumor cells, thereby reinstating endogenous immune recognition and tumor lysis. However, DAC has also been demonstrated to have direct effects on immune cells. In this study, we report that DAC inhibits γδ T cell proliferation. In addition, DAC increases the number of KIR2DL2/3-positive γδ T cells, which are less cytotoxic than the KIR2DL2/3-negative γδ T cells. We found that DAC upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances the binding of KIR2DL2/3 promoter to Sp-1 and activates KIR2DL2/3 gene expression. Our data demonstrated that DAC can inhibit the function of human γδ T cells at both cellular and molecular levels, which confirms and extrapolates the results of previous studies showing that DAC can negatively regulate the function of NK cells and αβ T cells of the immune system.

Epirubicin sequential natural killer cells enhanced the cytotoxicity to breast cancer cells in vitro

Meeting abstracts Anthracycline-based chemotherapy is a conventional therapy for breast cancer patients, but also negatively affects host immune function. When the host immune system does not work, chemotherapy and radiotherapy cannot kill the cancer cells efficiently. Therefore, improve the host