Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. The role of inflammation in DN has only recently been recognized. It has been shown that the NLRP3-inflammasome contributes to DN development by inducing interleukin (IL)-1β processing and secretion. In an effort to understand other IL-1β activating mechanism during DN development, we examined the role of the NLRC4-inflammasome in DN and found that NLRC4 is a parallel mechanism, in addition to the NLRP3-inflammasome, to induce pro-IL-1β processing and activation. We found that the expression of NLRC4 is elevated in DN kidneys. NLRC4-deficiency results in diminished DN disease progression, as manifested by a decrease in blood glucose and albumin excretion, as well as preserved renal histology. We further found that DN kidneys have increased F4/80+ macrophages, increased IL-1β production, and other signaling pathways related to kidney pathology such as activation of NF-κB and MAP kinase pathways, all of which were rescued by NLRC4-deficiency. This study demonstrates NLRC4-driven IL-1β production as critical for the progression of DN, which underscores the importance to target this pathway to alleviate this devastating disease.
Neutrophils play an essential role in the innate immune response to infection. Neutrophils migrate from the vasculature into the tissue in response to infection. Recently, a neutrophil cell surface receptor, CD177, was shown to help mediate neutrophil migration across the endothelium through interactions with PECAM1. We examined a publicly available gene array dataset of CD177 expression from human neutrophils following pulmonary endotoxin instillation. Among all 22,214 genes examined, CD177 mRNA was the most upregulated following endotoxin exposure. The high level of CD177 expression is also maintained in airspace neutrophils, suggesting a potential involvement of CD177 in neutrophil infiltration under infectious diseases. To determine the role of CD177 in neutrophils in vivo, we constructed a CD177-genetic knockout mouse model. The mice with homozygous deletion of CD177 have no discernible phenotype and no significant change in immune cells, other than decreased neutrophil counts in peripheral blood. We examined the role of CD177 in neutrophil accumulation using a skin infection model with Staphylococcus aureus. CD177 deletion reduced neutrophil counts in inflammatory skin caused by S. aureus. Mechanistically we found that CD177 deletion in mouse neutrophils has no significant impact in CXCL1/KC- or fMLP-induced migration, but led to significant cell death. Herein we established a novel genetic mouse model to study the role of CD177 and found that CD177 plays an important role in neutrophils.
Abstract: Triple-negative breast cancer (TNBC) is a heterogeneous disease with poorer outcomes compared to other breast cancer subtypes. Contributing to the worse prognosis in TNBC is the higher rates of relapse and rapid progression after relapse. Advances in targeted therapeutics and conventional chemotherapy for TNBC have been stymied due to the lack of specific targets. Moreover, the responses to chemotherapy in TNBC lack durability, partially accounting for the higher rates of relapse. Immunotherapy, notably immune-checkpoint blockade, has shown to improve survival and maintain robust antitumor responses in both hematologic and solid malignancies. Unlike lung cancer, melanoma, and bladder cancer, most breast cancers are not inherently immunogenic and typically have low T cell infiltration. However, among breast cancer subtypes, TNBC is characterized by greater tumor immune infiltrate and higher degree of stromal and intratumoral tumor-infiltrating lymphocytes (TILs), a predictive marker for responses to immunotherapy. Moreover, in TNBC, the high number of stromal TILs is predictive of more favorable survival outcomes and response to chemotherapy. Immunotherapy is being extensively explored in TNBC and clinical trials are showing some promising results. This article focuses on the rationale for immunotherapy in TNBC, to explore and discuss preclinical data, results from early clinical trials, and to summarize some ongoing trials. We will also discuss the potential application of immunotherapy in TNBC from a clinician's perspective. Keywords: triple-negative breast cancer, immunotherapy, PD-1/PDL-1 antibody, CTLA-4 antibody, checkpoint inhibitors, cancer vaccines
Abstract The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.
Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) is an oncofetal protein and has gained attention in cancer therapy since its initial discovery as a relatively specific surface antigen on B cell chronic lymphocytic leukemia (CLL) in 2008.The list of cancer types with ROR1 expression keeps growing, comprising, among others, malignant melanoma, breast cancer, and prostate cancer.It has been shown that ROR1 mediates several oncogenic pathways in a cancer type-and context-dependent manner.There are several ways to target ROR1 molecule, some of which have been in preclinical and clinical trials.We briefly summarize the oncogenic signaling pathways related to ROR1, as well as the update on ROR1-targeted therapies.
Abstract To better treat breast cancer patients, it is imperative to be able to predict breast cancer relapse and metastasis. Here, we identified the cluster of differentiation 177 (CD177) expression is positively correlated with relapse-free and metastasis-free survival of breast cancer patients. CD177 protein is highly expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Using mouse models, we found that CD177 suppresses breast cancer, primarily by forming a complex with E-Cadherin and b-Catenin at adherens junctions. The physical interaction prevents the activation of b-Catenin-mediated transcription by the canonical WNT signaling as demonstrated by a TOP-flash dual luciferase assay. In conclusion, we have identified CD177 as a novel breast cancer suppressor and uncovered a new regulatory mechanism for the canonical WNT/b-Catenin-mediated oncogenic signaling transduction. Citation Format: Paige N. Kluz, Ryan Kolb, Qing Xie, Nicholas Borcherding, Linna Wang, James P. De Andrade, Phillip M. Spanheimer, Wei Li, Katherine N. Gibson-Corley, Andy W. Tao, Sonia Sugg, Ronald J. Weigel, Weizhou Zhang. CD177 suppresses breast cancer progression by regulating the canonical WNT β-Catenin pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2017-5529
Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.
The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen's pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.
Abstract Clinical trials show promising outcomes for dogs with advanced solid tumors following treatment with immune checkpoint inhibitors (ICIs). Triple-negative breast cancer (TNBC) is very aggressive with very low response rates to ICIs. No study defines how canine TNBC interacts with the immune system within the tumor microenvironment, which is investigated in this study at the single cell level. Single cell RNA sequencing (scRNA-seq) datasets, including 6 groups of 30 dogs, were subject to integrated bioinformatic analysis. Immune modulatory TNBC subsets were identified by functional enrichment with immune-suppressive gene sets, including anti-inflammatory and M2-like macrophages. Key genes and immune-suppressive signaling pathways for TNBC included angiogenesis and leukocyte chemotaxis. Interactome analysis identified significant interactions between distinct subsets of cancer cells and effector T cells, suggesting T cell suppression. This is the first study to define immune-suppressive cancer cell subsets at the single-cell level, revealing potential mechanisms by which TNBC induces immune evasion in dogs.
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