A5056917171- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- vaccines and immunoinformatics approaches
- Biosimilars and Bioanalytical Methods
- Atherosclerosis and Cardiovascular Diseases
- Genetics, Aging, and Longevity in Model Organisms
- Advanced Biosensing Techniques and Applications
- Chemokine receptors and signaling
- interferon and immune responses
- Mitochondrial Function and Pathology
- Photosynthetic Processes and Mechanisms
- CRISPR and Genetic Engineering
- Immune cells in cancer
- Galectins and Cancer Biology
- RNA Research and Splicing
- Protein Tyrosine Phosphatases
- Cytomegalovirus and herpesvirus research
- MicroRNA in disease regulation
Ludwig Cancer Research
2013-2024
University Hospital of Lausanne
2016-2024
Swiss Cancer Center Léman
2024
University of Lausanne
2012-2023
McGill University
2008
Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel sequence-optimized HLA-A(*)0201/NY-ESO-1(157-165)-specific TCR variants with affinities lying within physiological boundaries preserve antigenic...
Through a rational design approach, we generated panel of HLA-A*0201/NY-ESO-1(157-165)-specific T cell receptors (TCR) with increasing affinities up to 150-fold from the wild-type TCR. Using these TCR variants which extend just beyond natural affinity range, along an extreme supraphysiologic one having 1400-fold enhanced affinity, and low-binding one, sought determine effect binding properties cognate peptide concentration on CD8(+) responsiveness. Major histocompatibility complexes (MHC)...
Anti-self/tumor T cell function can be improved by increasing TCR-peptide MHC (pMHC) affinity within physiological limits, but paradoxically further increases (Kd < 1 μM) lead to drastic functional declines. Using human CD8+ cells engineered with TCRs of incremental for the tumor antigen HLA-A2/NY-ESO-1, we investigated molecular mechanisms underlying this high-affinity–associated loss function. As compared expressing TCR affinities generating optimal = 5 μM), those supraphysiological μM 15...
The success of cancer immunotherapy depends in part on the strength antigen recognition by T cells. Here, we characterize cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities 371 CD8 clones specific for neoantigens, tumor-associated antigens (TAAs) or viral isolated from tumors blood patients healthy donors. cells exhibit stronger avidity than their counterparts. Relative to TAA, neoantigen-specific are higher and, consistently,...
Adoptive T-cell transfer of therapeutic TCR holds great promise to specifically kill cancer cells, but relies on modifying the patient's own T cells ex vivo before injection. The manufacturing in a tailor-made setting is long and expensive process which could be resolved by use universal cells. Currently, only Natural Killer (NK) cell line NK-92 FDA approved for use. In order expand their recognition ability, they were equipped with Chimeric Antigen Receptors (CARs). However, unlike CARs,...
Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured TCRs is a promising approach for clinical adoptive therapy, the aim to improve treatment efficacy. Despite numerous functional-based studies, little known about characteristics of TCR signaling (i.e. intensity, duration and amplification) regulatory mechanisms underlying optimal therapeutic responses. Using panel human SUP-T1 primary cells engineered incremental affinity against cancer-testis antigen NY-ESO-1, we found...
Abstract The avidity of the T-cell receptor (TCR) for antigenic peptides presented by peptide–MHC (pMHC) on cells is a key parameter cell-mediated immunity. Yet fundamental feature most tumor antigen-specific CD8+ T that this low. In study, we addressed need to identify and select tumor-specific highest avidity, which are greatest interest adoptive cell therapy in patients with cancer. To these rare cells, developed multimer technology, uses reversible Ni2+-nitrilotriacetic acid histidine...
Despite influencing many aspects of T cell biology, the kinetics receptor (TCR) binding to peptide-major histocompatibility molecules (pMHC) remain infrequently determined in patient monitoring or for adoptive therapy. Using specifically designed reversible fluorescent pMHC multimeric complexes, we performed a comprehensive study TCR-pMHC off-rates combined with various functional assays on large libraries self/tumor- and virus-specific CD8+ clones from melanoma patients healthy donors. We...
Cytotoxic CD8 T cells mediate immunity to pathogens and they are able eliminate malignant cells. Immunity viruses bacteria primarily involves bearing high affinity cell receptors (TCRs), which specific pathogen derived (non-self) antigens. Given the thorough elimination of self/tumor-antigen reactive by central peripheral tolerance mechanisms, anti-cancer mostly depends on TCRs with intermediate-to-low for self-antigens. Because this, a promising novel therapeutic approach increase efficacy...
Transgenic coexpression of a class I-restricted tumor antigen-specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity CD4+ cells. Reinforcement biophysical properties early TCR signaling explain how redirected cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated human CD8+ by single-cell RNA sequencing characterized them experimentally in bulk assays mouse xenograft model. TCR8...
Experimental models demonstrated that therapeutic induction of CD8 T cell responses may offer protection against tumors or infectious diseases providing cells have sufficiently high TCR/CD8:pMHC avidity for efficient Ag recognition and consequently strong immune functions. However, comprehensive characterization in clinically relevant situations has remained elusive. In this study, using the novel NTA-His tag-containing multimer technology, we quantified TCR:pMHC dissociation rates (koff)...
<h3>Background</h3> Affinity-optimized T cell receptor (TCR)-engineered lymphocytes targeting tumor antigens can mediate potent antitumor responses in cancer patients, but also bear substantial risks for off-target toxicities. Most preclinical studies have focused on to antigen-specific stimulation. In contrast, little is known the regulation of responsiveness through continuous TCR triggering and consequent tonic signaling. Here, we addressed question whether increasing affinity lead...
Cdc25 phosphatases are key positive cell cycle regulators that coordinate divisions with growth and morphogenesis in many organisms. Intriguingly C. elegans, two cdc-25.1(gf) mutations induce tissue-specific temporally restricted hyperplasia the embryonic intestinal lineage, despite stabilization of mutant CDC-25.1 protein every blastomere. We investigated molecular basis underlying CDC-25.1(gf) its associated phenotype. found both affect a canonical β-TrCP phosphodegron motif, while F-box...
CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e. avidity. A current challenge in onco-immunology lies evaluation of vaccine protocols selecting for tumor-specific T-cells highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated impact peptide CpG/adjuvant doses quality vaccine-induced relation avidity functional responses treated melanoma patients. Using TCR-pMHC measurements combined...
Recruitment and activation of CD8 T cells occur through specific triggering cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, molecular binding affinities between peptide HLA, TCR peptide:HLA both impact functional outcomes. However, how their individual combined effects modulate immunogenicity overall responsiveness has not been investigated systematically. Here, we established two panels tumor variants...
The maternal contribution of gene products enables embryos to initiate their developmental program in the absence zygotic expression. In Caenorhabditis elegans, CDC-25.1 levels are tightly regulated promote early cell divisions, while stabilization this phosphatase by gain-of-function mutations gives rise intestinal-specific hyperplasia. To identify regulators and/or function, we performed a modifier screen cdc-25.1(gf)-dependent One isolated suppressor mutants possesses donor splice site...
Abstract The potency of cellular immune responses strongly depends on T cell avidity to antigen. Yet, functional measurements are rarely performed in patients, mainly due the technical challenges characterizing heterogeneous cells. mean can be determined by IFN-γ Elispot assay, with titrated amounts peptide. Using this we developed a method revealing heterogeneity avidity, represented steepness/hillslope peptide titration curve, documented proof principle experiments and mathematical...
T cells targeting epitopes in infectious diseases or cancer play a central role spontaneous and therapy-induced immune responses. T-cell epitope recognition is mediated by the binding of T-Cell Receptor (TCR) TCRs recognizing clinically relevant are promising for based therapies. Starting from one few known cancer-testis antigen NY-ESO-1 157-165 epitope, we built large phage display libraries with randomized Complementary Determining Region 3 β chain. The TCR were panned against which...
Cytotoxic CD8+ T cells are able to specifically recognize and kill target through specific interaction between their cell receptors (TCRs) small immunogenic peptides (antigens) presented by major histocompatibility complex (MHC) molecules. The antigen recognition capacity in vitro lytic activity of antigen-specific cytotoxic can be assessed functionally the so-called chromium 51 (51Cr) release assay, which was developed almost 50 years ago our institution (Brunner et al., 1968)....
It is known that for achieving high affinity antibody responses, vaccines must be optimized antigen dose/density, and the prime/boost interval should at least 4 weeks. Similar knowledge lacking generating avidity T-cell responses. The functional (FA) of T cells, describing responsiveness to peptide, associated with quality effector function protective capacity in vivo. Despite its importance, FA rarely determined vaccination studies. We addressed question whether different time intervals...
T cells protect us from a large number of infectious diseases. Several lines evidence indicate that can also eliminate malignant and alter the progression tumors. These two types immune responses were traditionally viewed to involve different or qualities cells. Pathogen-specific thought be predominantly mediated by bearing high affinity cell receptors (TCRs) specific for microbial-derived antigens. In contrast, anti-tumor immunity autoimmune diseases normally TCRs with intermediate-to-low...