A5103210662- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Immune Response and Inflammation
- Cytomegalovirus and herpesvirus research
- Cell death mechanisms and regulation
- Reproductive System and Pregnancy
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Cancer Immunotherapy and Biomarkers
- Viral-associated cancers and disorders
- Antimicrobial Peptides and Activities
- interferon and immune responses
- NF-κB Signaling Pathways
- T-cell and Retrovirus Studies
- Ocular Oncology and Treatments
- Retinoids in leukemia and cellular processes
- Neuroblastoma Research and Treatments
- Pediatric health and respiratory diseases
- Cancer, Hypoxia, and Metabolism
- Toxoplasma gondii Research Studies
- Radiopharmaceutical Chemistry and Applications
- Reproductive tract infections research
Molecular Partners (Switzerland)
2020-2021
Roche (Switzerland)
2013-2020
Institute of Cytology and Genetics
2018
Siberian Branch of the Russian Academy of Sciences
2018
Novosibirsk State University
2018
Johns Hopkins University
2007-2013
Engelhardt Institute of Molecular Biology
2013
Johns Hopkins Medicine
2007-2010
Karolinska Institutet
1999-2008
University of Toronto
2004-2005
Dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors, also referred to as immune checkpoints. Yet, their relative functional significance different cancer types remains incompletely understood. In this study, we provide comprehensive characterization the diversity patterns receptors on tumor-infiltrating from patients with non-small cell lung cancer. spite large heterogeneity observed amount PD-1, Tim-3,...
Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting a tumor stroma or antigen: FAP-4-1BBL (RG7826) CD19-4-1BBL. In the...
IFN-γ regulates the immunogenicity of target cells by increasing their expression HLA class I molecules. This facilitates T cell receptor–mediated recognition CD8+ but decreases sensitivity to lysis NK due engagement inhibitory receptors. In this study, short-term tumor lines from patients with advanced ovarian carcinomas were established. We demonstrate paradoxical finding that treatment these carcinoma (OVACs) resulted in resistance peptide- and allospecific cells. Blocking experiments...
Abstract Mesenchymal stem cells (MSCs), isolated from adult human bone marrow, have immunomodulatory properties. The functional outcomes of MSCs–CTL interactions remain poorly characterized. In this study, we demonstrate that MSCs resistant to CTL lysis, even after pulsing with the specific synthetic peptide at high concentrations, in spite surface expression relevant MHC class I allele. were also much less sensitive lysis by an allo-specific clone as compared HLA-matched lymphoblastoid cell...
Abstract By using mice genomically lacking IFN-γR, IL-12, perforin, and recombination-activating gene-1 (RAG-1), we analyzed the regulation importance of IFN-γ in control infection with Chlamydia pneumoniae. IL-12 participates resistance to C. pneumoniae, probably by regulating protective levels mRNA. In turn, is necessary for increased IL-12p40 mRNA accumulation that occurs lungs during suggesting a positive feedback between these two cytokines. experiments including RAG-1−/−/IFN-γR−/−...
IFN-γ regulates the immunogenicity of target cells by increasing their expression HLA class I molecules. This facilitates T cell receptor–mediated recognition CD8+ but decreases sensitivity to lysis NK due engagement inhibitory receptors. In this study, short-term tumor lines from patients with advanced ovarian carcinomas were established. We demonstrate paradoxical finding that treatment these carcinoma (OVACs) resulted in resistance peptide- and allospecific cells. Blocking experiments...
The compromise between affinity and specificity in TCR-dependent targeting of HLA-restricted tumor-associated antigens presents a significant challenge developing efficacious immunotherapies. As such, T cell engagers which circumvent these limitations are particular interest. We have established process to generate bispecific Designed Ankyrin Repeat Proteins (DARPins) that simultaneously target HLA-I molecules complex with peptides CD3ϵ. High-affinity HLA-A*0201/NY-ESO1 157-165 -specific...
Abstract Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive triggering induced bystander T or a Fas-specific agonistic antibody; this could be ascribed tumor counterattack against general the apoptosis. Treatment with inhibitors metalloproteases rendered uveal melanomas sensitive Fas-mediated cytotoxicity. Metalloprotease did affect expression increased...
Bim, a proapoptotic BH3-only member of the Bcl-2 protein family, is required for central and peripheral deletion T lymphocytes. Mechanisms regulating Bim activity in cells remain poorly understood. We show that expression up-regulated human after polyclonal or specific cell receptor triggering. Induction was affected by agonistic potency MHC:peptide ligands. Peptides failed to induce expression, apoptosis cells, whereas partially ligands, which trigger death receptor-independent...
The TCR repertoire of a peptide-specific HLA A11-restricted CTL response to persistent infection with EBV was followed for period 57 mo. Sequencing V alpha and beta chains alanine scanning mutagenesis analysis 83 clones isolated in five reactivation experiments demonstrated that this is composed at least four distinct clonotypes are constantly reactivated from donor's blood express structurally heterogeneous TCRs. Target cell recognition CD8 blocking indicate the possess different avidity...
We have compared the subunit composition and enzymatic activity of purified 26S proteasomes from Burkitt's lymphoma (BL) cells in vitro EBV-transformed lymphoblastoid cell lines (LCLs) normal B origin. Low expression IFN-gamma-regulated beta low molecular mass polypeptide (Lmp)2, Lmp7, MECL-1 was demonstrated a panel seven BL that express germinal center phenotype original tumor. Coexpression Lmp2 Lmp7 with constitutively expressed subunits delta MB1 by immunoprecipitation two-dimensional...
Abstract IFN-γ, a pleiotropic immune regulator, is implicated in both tumor surveillance and selection of variants resistant to control, i.e., immunoediting. In uveal melanoma patients, elevated serum levels IFN-γ correlate with the spread metastasis represent negative prognostic marker. Treatment boosted MHC class I presentation machinery cells but suppressed their I-restricted CTL lysis. Tumor exposed efficiently activated specific were less susceptible permeabilization by perforin...
T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into microenvironment, imprints on activity TCBs. We performed comprehensive analysis activation effector functions tumor-infiltrating (TILs) in different types, upon stimulation by TCB targeting folate receptor 1 CD3 (FolR1-TCB). observed considerable...
Tumor cells escape immune eradication through multiple mechanisms, including loss of antigenicity and local suppression effector lymphocytes. To counteract these obstacles, we aimed to direct the unique cytomegalovirus (CMV)-specific surveillance against tumor cells. We developed a novel generation fusion proteins composed antigen-specific full immunoglobulin connected single major histocompatibility class I complex bearing covalently linked virus-derived peptide (pMHCI-IgG). Here, show that...
We investigated the expression of interferon gamma (IFN-γ)–regulated subunits and enzymatic activity proteasomes purified from tumor-derived normal B lymphocytes representing different stages B-cell activation/differentiation. The catalytic β (Lmp2 Lmp7) regulatory (PA28α PA28β) were expressed at equally high levels in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs), freshly isolated B-chronic lymphocytic leukemia (B-CLL) cells CD23− lymphocytes. Lmp2 Lmp7 selectively...
Abstract BCR-triggering shown as the first known B-cell-specific signal enhancing cellular sensitivity to TRAIL. TRAIL is cause death in tumor cells, but physiological regulation of its activity remains poorly characterized. We demonstrate that BCR triggering sensitizes transformed centroblast-like BL cells and peripheral blood memory B TRAIL-mediated apoptosis. The sensitization correlated with surface down-regulation intracellular retention TRAIL-R4, along changes expression several Bcl-2...
BACKGROUND Benign prostatic hyperplasia (BPH) is the most common benign adenoma and prostate cancer frequent malignancy in men over 50 years of age Western world, where it remains a significant health problem. Prostate lesions are known to contain immune cells, which may contribute control tumor progression. However, due their low numbers restricted access necessary material difficult isolate cells from tissue characterize immunological features. METHODS An efficient robust method was...
Abstract Based on the unprecedented clinical efficacy of PD-1/PD-L1 pathway checkpoint inhibitors (CPI), non-redundant immune checkpoints like TIM-3, LAG-3, TIGIT or BTLA are currently being targeted, by combinatorial approaches using monospecific bispecific antibodies. Up-regulation TIM-3 has been described as an adaptive CPI resistance mechanism, and internal prevalence data archival samples CPI-naïve -experienced patients showed co-expression PD-1 in various tumor types, consistent with...
After specific activation, CD8 + cytotoxic T lymphocytes (CTLs) enter a refractory state termed activation-induced nonresponsiveness (AINR) that is characterized by the inability of cells to respond secondary stimulus. Here, we show cell receptor triggering results in rapid degradation src-family protein kinase lck through mechanism proteasome- and lysosome-independent, sensitive cysteine protease inhibitors, distinct from pathways involved ZAP-70 or ζ-chain CD3 complex. Pharmacologic...