38 research outputs found
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Immunization with a Peptide Containing MHC Class I and II Epitopes Derived from the Tumor Antigen SIM2 Induces an Effective CD4 and CD8 T-Cell Response
Here, we sought to determine whether peptide vaccines designed harbor both class I as well as class II restricted antigenic motifs could concurrently induce CD4 and CD8 T cell activation against autologous tumor antigens. Based on our prior genome-wide interrogation of human prostate cancer tissues to identify genes over-expressed in cancer and absent in the periphery, we targeted SIM2 as a prototype autologous tumor antigen for these studies. Using humanized transgenic mice we found that the 9aa HLA-A*0201 epitope, SIM2237–245, was effective at inducing an antigen specific response against SIM2-expressing prostate cancer cell line, PC3. Immunization with a multi-epitope peptide harboring both MHC-I and MHC-II restricted epitopes induced an IFN-γ response in CD8 T cells to the HLA-A*0201-restricted SIM2237–245 epitope, and an IL-2 response by CD4 T cells to the SIM2240–254 epitope. This peptide was also effective at inducing CD8+ T-cells that responded specifically to SIM2-expressing tumor cells. Collectively, the data presented in this study suggest that a single peptide containing multiple SIM2 epitopes can be used to induce both a CD4 and CD8 T cell response, providing a peptide-based vaccine formulation for potential use in immunotherapy of various cancers
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The Scavenger Receptor MARCO Modulates TLR-Induced Responses in Dendritic Cells
The scavenger receptor MARCO mediates macrophage recognition and clearance of pathogens and their polyanionic ligands. However, recent studies demonstrate MARCO expression and function in dendritic cells, suggesting MARCO might serve to bridge innate and adaptive immunity. To gain additional insight into the role of MARCO in dendritic cell activation and function, we profiled transcriptomes of mouse splenic dendritic cells obtained from MARCO deficient mice and their wild type counterparts under resting and activating conditions. In silico analysis uncovered major alterations in gene expression in MARCO deficient dendritic cells resulting in dramatic alterations in key dendritic cell-specific pathways and functions. Specifically, changes in CD209, FCGR4 and Complement factors can have major consequences on DC-mediated innate responses. Notably, these perturbations were magnified following activation with the TLR-4 agonist lipopolysaccharide. To validate our in silico data, we challenged DC‘s with various agonists that recognize all mouse TLRs and assessed expression of a set of immune and inflammatory marker genes. This approach identified a differential contribution of MARCO to TLR activation and validated a major role for MARCO in mounting an inflammatory response. Together, our data demonstrate that MARCO differentially affects TLR-induced DC activation and suggest targeting of MARCO could lead to different outcomes that depend on the inflammatory context encountered by DC
NAD+ protects against EAE by regulating CD4+ T-cell differentiation
CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases
Immunological Complexity of the Prostate Cancer Microenvironment Influences the Response to Immunotherapy.
Prostate cancer is one of the most common cancers in men and a leading cause of cancer-related death. Recent advances in the treatment of advanced prostate cancer, including the use of more potent and selective inhibitors of the androgen signaling pathway, have provided significant clinical benefit for men with metastatic castration-resistant prostate cancer (mCRPC). However, most patients develop progressive lethal disease, highlighting the need for more effective treatments. One such approach is immunotherapy, which harness the power of the patient\u27s immune system to identify and destroy cancer cells through the activation of cytotoxic CD8 T cells specific for tumor antigens. Although immunotherapy, particularly checkpoint blockade, can induce significant clinical responses in patients with solid tumors or hematological malignancies, minimal efficacy has been observed in men with mCRPC. In the current review, we discuss our current understanding of the immunological complexity of the immunosuppressive prostate cancer microenvironment, preclinical models of prostate cancer, and recent advances in immunotherapy clinical trials to improve outcomes for men with mCRPC
Human SIM2 gene expression analysis in various cancers.
<p>SIM2 gene expression data were extracted from the Oncomine Research Edition. Microarray datasets that show a 2-fold change in SIM2 expression between cancer and control groups and a p value<0.01 are highlighted. (<b>A</b>) Comparison of SIM2 gene expression between cancer and control specimens. Red color indicates SIM2 overexpression and the blue color indicates SIM2 down-regulation in cancer. Numbers in the boxes indicate the number of datasets showing statistical significance. Box plots were obtained from the datasets selected in (<b>A</b>) to highlight significant overexpression of SIM2 in Prostate Carcinoma (1. Prostate Gland (n = 23), 2. Prostate Carcinoma (n = 65); <i>P</i> = 2.41×10<sup>−14</sup>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093231#pone.0093231-Yu1" target="_blank">[40]</a>) (<b>B</b>); Colon Carcinoma (1. Colon (n = 10), 2. Colon Carcinoma (n = 5); P = 1.65×10<sup>−12 </sup><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093231#pone.0093231-Skrzypczak1" target="_blank">[41]</a>). (<b>C</b>); Breast Carcinoma (1. Breast (n = 4), 2. Invasive Breast Carcinoma (n = 154); P = 2.25×10<sup>−4</sup>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093231#pone.0093231-Gluck1" target="_blank">[42]</a>) (<b>D</b>); Oligodendroglioma (1. Brain (n = 23), 2. Oligodendroglioma (n = 50); P = 3.31×10<sup>−9 </sup><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093231#pone.0093231-Sun1" target="_blank">[43]</a>) (<b>E</b>); and Pancreatic Carcinoma (1. Pancreas (n = 16), 2. Pancreatic Carcinoma (n = 36); P = 3.01×10<sup>−7 </sup><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093231#pone.0093231-Pei1" target="_blank">[44]</a>) (<b>F</b>).</p
IFN-γ production by CD8 T-cells from SIM2-immunized mice.
<p>Mice were immunized with either SIM2<sub>237</sub>, SIM2<sub>237</sub>+HBV<sub>128</sub>, SIM2<sub>237</sub>+SIM2<sub>240–254</sub> or SIM2<sub>230–256</sub>. Splenocytes were harvested and incubated overnight with T2 cells loaded with the SIM2<sub>237</sub> peptide. IFN-γ was measured by flow cytometry. FACS plots show the median IFN-γ production for each group (A) and replicate data obtained from each group (B).</p
Splenocytes from SIM2<sub>230–256</sub>-immunized mice response to PC3-A2.1 cells.
<p>Splenocytes from HHD mice immunized with HBV and various SIM2<sub>230–256</sub> peptides or HBV alone were co-cultured with PC3, PC3-A2.1 (<b>A</b>) or LNCaP (<b>B</b>). Production of IFN-γ by splenocytes in response to these tumor cell lines was assessed by ELISPOT. Data is representative of 2 experiments and shows mean ± standard deviation.</p
SIM2<sub>230–256</sub> induces an IFN-γ and CD4 IL-2 response.
<p>IFN-γ production by splenocytes in mice immunized with various treatments. Mice were immunized with either the 9aa SIM2<sub>237</sub> epitope combined with HBV or SIM2<sub>240–254</sub>, or the SIM2<sub>230–256</sub> peptide alone. IFN-γ production was measured by ELISPOT. IL-2 production by CD4 T-cells. CD4 T-cells were sorted from the spleens of immunized mice and tested for reactivity to HBV<sub>128</sub> and SIM2<sub>240–254</sub> by IL-2 ELISPOT.</p