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1.
Cancer Cell ; 42(4): 568-582.e11, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38490213

ABSTRACT

Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying ß2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8+ T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.


Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Animals , Mice , Histocompatibility Antigens Class I/genetics , Interleukin-2/genetics , Interleukin-2/immunology , Neoplasms/genetics , RNA, Messenger , Tumor Microenvironment
2.
Cancer Immunol Res ; 12(2): 144-148, 2024 02 02.
Article in English | MEDLINE | ID: mdl-38231158

ABSTRACT

From September 20 to 23, 2023, the Seventh International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the European Network for Cancer Immunotherapy (ENCI), and the American Association for Cancer Research (AACR) in Milan, Italy. The four-day event covered the latest advances in cancer immunology and immunotherapy.


Subject(s)
Neoplasms , Humans , Neoplasms/therapy , Immunotherapy
3.
Hum Vaccin Immunother ; 18(6): 2124785, 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36222759

ABSTRACT

The 19th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe's cancer immunotherapy meeting, was the first in-person event organized by CIMT since the beginning of the COVID-19 pandemic. As a hybrid event from May 10-12, the meeting attracted 920 academic and clinical professionals from over 40 countries, who met to discuss the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2022.


Subject(s)
COVID-19 , Neoplasms , Humans , Pandemics , Neoplasms/therapy , COVID-19/therapy , Immunotherapy , Tumor Microenvironment
4.
Anal Chem ; 94(25): 8966-8974, 2022 06 28.
Article in English | MEDLINE | ID: mdl-35708243

ABSTRACT

Atmospheric particles and droplets contain numerous organic substances, some of which form complexes with metal ions, significantly affecting bulk physicochemical properties and chemical reactivity. However, the detection and identification of complexing agents and their corresponding metal complexes remains an analytical challenge. In this study, we developed an LC/HRMS nontarget screening (NTS) approach which allows the selective detection of complexing agents in aerosol particle extracts and rainwater. To achieve this, a T-junction is installed between the LC outlet and the ion source, and a FeCl3 solution is added for postcolumn complexation. The resulting mass spectra are screened for the three characteristic iron(III)-complexes [M - H + FeCl3]-, [M - 2H + FeCl2]-, and [M - 3H + FeCl]- with mass differences (Δm/z) between the complexing agent and the iron complex of 160.8416, 124.8648, and 89.8959, respectively. Up to 29 di- or tricarboxylic acids were identified as complexing agents in aerosol particle samples from two different sites (Melpitz, Germany, and Wangdu, China) at concentrations as low as 50 nM. Thirteen complexing agents were detected even in measurements without postcolumn iron addition from complexation with background Fe3+ traces from the analytical system. At least for the highest concentrated complexing agents, the proposed screening approach can thus be exploited in a NTS approach without any device modification. Besides carboxylic acids, 4-nitrophenol and 4-nitrocatechol were identified as further complexing agents, demonstrating the applicability of the approach to other matrices and to a range of different complexing agents.


Subject(s)
Ferric Compounds , Iron , Aerosols , Carboxylic Acids/chemistry , Iron/chemistry , Mass Spectrometry/methods
5.
Mol Cancer ; 20(1): 69, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33858437

ABSTRACT

Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.


Subject(s)
Genetic Therapy , Immunotherapy , Neoplasms/etiology , Neoplasms/therapy , RNA, Messenger/administration & dosage , Animals , Antibodies/genetics , Antibodies/immunology , Antigen Presentation/immunology , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Biomarkers, Tumor , Cancer Vaccines/administration & dosage , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Genetic Therapy/methods , Humans , Immunologic Factors/genetics , Immunotherapy/methods , Neoplasms/pathology , RNA, Messenger/chemistry , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
7.
Nat Ecol Evol ; 3(4): 539-551, 2019 04.
Article in English | MEDLINE | ID: mdl-30858594

ABSTRACT

Species distributions and abundances are undergoing rapid changes worldwide. This highlights the significance of reliable, integrated information for guiding and assessing actions and policies aimed at managing and sustaining the many functions and benefits of species. Here we synthesize the types of data and approaches that are required to achieve such an integration and conceptualize 'essential biodiversity variables' (EBVs) for a unified global capture of species populations in space and time. The inherent heterogeneity and sparseness of raw biodiversity data are overcome by the use of models and remotely sensed covariates to inform predictions that are contiguous in space and time and global in extent. We define the species population EBVs as a space-time-species-gram (cube) that simultaneously addresses the distribution or abundance of multiple species, with its resolution adjusted to represent available evidence and acceptable levels of uncertainty. This essential information enables the monitoring of single or aggregate spatial or taxonomic units at scales relevant to research and decision-making. When combined with ancillary environmental or species data, this fundamental species population information directly underpins a range of biodiversity and ecosystem function indicators. The unified concept we present links disparate data to downstream uses and informs a vision for species population monitoring in which data collection is closely integrated with models and infrastructure to support effective biodiversity assessment.


Subject(s)
Biodiversity , Animals , Models, Theoretical
8.
Oncoimmunology ; 8(3): 1553478, 2019.
Article in English | MEDLINE | ID: mdl-30723585

ABSTRACT

Cancer-associated mutations, mostly single nucleotide variations, can act as neoepitopes and prime targets for effective anti-cancer T-cell immunity. T cells recognizing cancer mutations are critical for the clinical activity of immune checkpoint blockade (ICB) and they are potent vaccine antigens. High frequencies of mutation-specific T cells are rarely spontaneously induced. Hence, therapies that broaden the tumor specific T-cell response are of interest. Here, we analyzed neoepitope-specific CD8+ T-cell responses mounted either spontaneously or after immunotherapy regimens, which induce local tumor inflammation and cell death, in mice bearing tumors of the widely used colon carcinoma cell line CT26. A comprehensive immune reactivity screening of 2474 peptides covering 628 transcribed CT26 point mutations was conducted. All tested treatment regimens were found to induce a single significant CD8+ T-cell response against a non-synonymous D733A point mutation in the Smc3 gene. Surprisingly, even though Smc3 D733A turned out to be the immune-dominant neoepitope in CT26 tumor bearing mice, neither T cells specific for this neoepitope nor their T cell receptors (TCRs) were able to recognize or lyse tumor cells. Moreover, vaccination with the D733A neoepitope did not result in anti-tumoral activity despite induction of specific T cells. This is to our knowledge the first report that neoepitope specific CD8+ T cells primed by tumor-released antigen exposure in vivo can be functionally irrelevant.

9.
J Diabetes Sci Technol ; 13(2): 261-267, 2019 03.
Article in English | MEDLINE | ID: mdl-30241444

ABSTRACT

In the last 10 years tremendous progress has been made in the development of artificial pancreas (AP) systems for people with type 1 diabetes (T1D). The pan-European consortium CLOSE (Automated Glu cose Contro l at H ome for People with Chronic Disea se) is aiming to develop integrated AP solutions (APplus) tailored to the needs of people with type 2 diabetes (T2D). APplus comprises a product and service package complementing the AP system by obligatory training as well as home visits and telemedical consultations on demand. Outcome predictors and performance indicators shall help to identify people who could benefit most from AP usage and facilitate the measurement of AP impact in diabetes care. In a first step CLOSE will establish a scalable APplus model case working at the interface between patients, homecare service providers, and payers in France. CLOSE will then scale up APplus by pursuing geographic distribution, targeting additional audiences, and enhancing AP functionalities and interconnectedness. By being part of the European Institute of Innovation and Technology (EIT) Health public-private partnership, CLOSE is committed to the EIT "knowledge triangle" pursuing the integrated advancement of technology, education, and business creation. Putting stakeholders, education, and impact into the center of APplus advancement is considered key for achieving wide AP use in T2D care.


Subject(s)
Blood Glucose Self-Monitoring/instrumentation , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Insulin Infusion Systems , Pancreas, Artificial , Animals , Biomarkers , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Equipment Design , Europe , Humans , Insulin Infusion Systems/adverse effects , Pancreas, Artificial/adverse effects , Research Design , Stakeholder Participation , Treatment Outcome
11.
PLoS Biol ; 16(12): e2006841, 2018 12.
Article in English | MEDLINE | ID: mdl-30513079

ABSTRACT

Human use of the land (for agriculture and settlements) has a substantial negative effect on biodiversity globally. However, not all species are adversely affected by land use, and indeed, some benefit from the creation of novel habitat. Geographically rare species may be more negatively affected by land use than widespread species, but data limitations have so far prevented global multi-clade assessments of land-use effects on narrow-ranged and widespread species. We analyse a large, global database to show consistent differences in assemblage composition. Compared with natural habitat, assemblages in disturbed habitats have more widespread species on average, especially in urban areas and the tropics. All else being equal, this result means that human land use is homogenizing assemblage composition across space. Disturbed habitats show both reduced abundances of narrow-ranged species and increased abundances of widespread species. Our results are very important for biodiversity conservation because narrow-ranged species are typically at higher risk of extinction than widespread species. Furthermore, the shift to more widespread species may also affect ecosystem functioning by reducing both the contribution of rare species and the diversity of species' responses to environmental changes among local assemblages.


Subject(s)
Agriculture/methods , Biodiversity , Conservation of Natural Resources/methods , Animals , Ecosystem , Humans , Natural Resources
12.
Hum Vaccin Immunother ; 14(12): 2864-2873, 2018.
Article in English | MEDLINE | ID: mdl-30111232

ABSTRACT

The 16th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe's largest meeting series of its kind, took place in Mainz, Germany from 15-17 May, 2018. Cutting-edge advancements in cancer immunotherapy were discussed among more than 700 scientists under the motto "Pushing Frontiers in Cancer Immunotherapy". This meeting report is a summary of some of the CIMT 2018 highlights.


Subject(s)
Immunotherapy , Neoplasms/therapy , Animals , Congresses as Topic , Disease Models, Animal , Drug Therapy, Combination , Humans , Tumor Microenvironment , Vaccination , Xenograft Model Antitumor Assays
13.
Mol Biotechnol ; 60(10): 727-735, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30076531

ABSTRACT

In this study, we present a multiparameter screening procedure for the identification of target-specific antibodies with prescribed properties. Based on B cell receptor gene repertoires from transgenic rats, yeast surface display libraries were generated, and high-affinity human antibodies were readily isolated. We demonstrate that specific desirable features, i.e., species' cross-reactivity and a broad epitope coverage can be integrated into the screening procedure using high-throughput fluorescence-activated cell sorting. We show that the applied screening stringencies translate directly into binding properties of isolated human antibody variants.


Subject(s)
Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/isolation & purification , Cell Separation/methods , Flow Cytometry/methods , Saccharomyces cerevisiae/growth & development , Animals , Antibodies, Monoclonal/metabolism , Antibody Affinity , Cell Line , Cell Surface Display Techniques , Cloning, Molecular , Female , Humans , Male , Peptide Library , Rats , Rats, Transgenic , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism
14.
Methods Mol Biol ; 1685: 311-331, 2018.
Article in English | MEDLINE | ID: mdl-29086318

ABSTRACT

Fluorescence-activated cell sorting (FACS) in combination with yeast surface display (YSD) has proven to be a valuable tool for the engineering of antibodies. It enables the fast and robust identification and isolation of candidates with prescribed characteristics from combinatorial libraries. A novel application for FACS and YSD that has recently evolved addresses the engineering of antibodies toward pH-switchable antigen binding, aiming at reduced binding at acidic pH, compared to neutral pH. Therefore, we give guidance for the incorporation of such pH switches into antibody variable domains using combinatorial histidine scanning libraries. The protocol describes a flow cytometric sorting technique for the enrichment of antigen-specific molecules. Moreover, we provide information on how to screen the obtained antibody pools from initial sorting to isolate and characterize pH-sensitive variants.


Subject(s)
Cell Separation/methods , Flow Cytometry/methods , Immunoglobulin Fragments/isolation & purification , Saccharomyces cerevisiae/growth & development , Cloning, Molecular , Histidine/chemistry , Humans , Hydrogen-Ion Concentration , Immunoglobulin Fragments/metabolism , Peptide Library , Protein Engineering/methods , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism
16.
N Biotechnol ; 39(Pt B): 167-173, 2017 Oct 25.
Article in English | MEDLINE | ID: mdl-28137467

ABSTRACT

Bispecific IgG-like antibodies can simultaneously interact with two epitopes on the same or on different antigens. Therefore, these molecules facilitate novel modes of action, which cannot be addressed by conventional monospecific IgGs. However, the generation of such antibodies still appears to be demanding due to their specific architecture comprising four different polypeptide chains that need to assemble correctly. This review focusses on different strategies to circumvent this issue or to enforce a correct chain association with a focus on common-chain bispecific antibodies.


Subject(s)
Antibodies, Bispecific/metabolism , Protein Engineering/methods , Animals , Humans , Immunoglobulin Heavy Chains , Immunoglobulin Light Chains/metabolism , Protein Multimerization
17.
Protein Eng Des Sel ; 30(4): 291-301, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28062646

ABSTRACT

Bispecific antibodies (bsAbs) pave the way for novel therapeutic modes of action along with potential benefits in several clinical applications. However, their generation remains challenging due to the necessity of correct pairings of two different heavy and light chains and related manufacturability issues. We describe a generic approach for the generation of fully human IgG-like bsAbs. For this, heavy chain repertoires from immunized transgenic rats were combined with either a randomly chosen common light chain or a light chain of an existing therapeutic antibody and screened for binders against tumor-related targets CEACAM5 and CEACAM6 by yeast surface display. bsAbs with subnanomolar affinities were identified, wherein each separate binding arm mediated specific binding to the respective antigen. Altogether, the described strategy represents a combination of in vivo immunization with an in vitro selection method, which allows for the integration of existing therapeutic antibodies into a bispecific format.


Subject(s)
Antibodies, Bispecific , Antibodies, Neoplasm , Single-Chain Antibodies , Animals , Antibodies, Bispecific/biosynthesis , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/genetics , Antibodies, Neoplasm/biosynthesis , Antibodies, Neoplasm/genetics , Antigens, CD , Carcinoembryonic Antigen , Cell Adhesion Molecules/antagonists & inhibitors , GPI-Linked Proteins/antagonists & inhibitors , Humans , Mice , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Single-Chain Antibodies/biosynthesis , Single-Chain Antibodies/chemistry , Single-Chain Antibodies/genetics
18.
J Biol Chem ; 291(39): 20417-26, 2016 09 23.
Article in English | MEDLINE | ID: mdl-27493205

ABSTRACT

Transglutaminase from Streptomyces mobaraensis (MTG) is an important enzyme for cross-linking and modifying proteins. An intrinsic substrate of MTG is the dispase autolysis-inducing protein (DAIP). The amino acid sequence of DAIP contains 5 potential glutamines and 10 lysines for MTG-mediated cross-linking. The aim of the study was to determine the structure and glutamine cross-linking sites of the first physiological MTG substrate. A production procedure was established in Escherichia coli BL21 (DE3) to obtain high yields of recombinant DAIP. DAIP variants were prepared by replacing four of five glutamines for asparagines in various combinations via site-directed mutagenesis. Incorporation of biotin cadaverine revealed a preference of MTG for the DAIP glutamines in the order of Gln-39 ≫ Gln-298 > Gln-345 ∼ Gln-65 ≫ Gln-144. In the structure of DAIP the preferred glutamines do cluster at the top of the seven-bladed ß-propeller. This suggests a targeted cross-linking of DAIP by MTG that may occur after self-assembly in the bacterial cell wall. Based on our biochemical and structural data of the first physiological MTG substrate, we further provide novel insight into determinants of MTG-mediated modification, specificity, and efficiency.


Subject(s)
Bacterial Proteins/metabolism , Streptomyces/metabolism , Transglutaminases/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Escherichia coli/chemistry , Escherichia coli/genetics , Escherichia coli/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Streptomyces/chemistry , Streptomyces/genetics , Transglutaminases/chemistry , Transglutaminases/genetics
19.
Ecol Lett ; 19(9): 1009-22, 2016 09.
Article in English | MEDLINE | ID: mdl-27358193

ABSTRACT

We introduce a novel framework for conceptualising, quantifying and unifying discordant patterns of species richness along geographical gradients. While not itself explicitly mechanistic, this approach offers a path towards understanding mechanisms. In this study, we focused on the diverse patterns of species richness on mountainsides. We conjectured that elevational range midpoints of species may be drawn towards a single midpoint attractor - a unimodal gradient of environmental favourability. The midpoint attractor interacts with geometric constraints imposed by sea level and the mountaintop to produce taxon-specific patterns of species richness. We developed a Bayesian simulation model to estimate the location and strength of the midpoint attractor from species occurrence data sampled along mountainsides. We also constructed midpoint predictor models to test whether environmental variables could directly account for the observed patterns of species range midpoints. We challenged these models with 16 elevational data sets, comprising 4500 species of insects, vertebrates and plants. The midpoint predictor models generally failed to predict the pattern of species midpoints. In contrast, the midpoint attractor model closely reproduced empirical spatial patterns of species richness and range midpoints. Gradients of environmental favourability, subject to geometric constraints, may parsimoniously account for elevational and other patterns of species richness.


Subject(s)
Biodiversity , Ecosystem , Models, Biological , Animals , Bayes Theorem , Insecta/physiology , Plant Physiological Phenomena , Vertebrates/physiology
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