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Article ; Online: Immune pressure sculps tumor cells and trims high-quality mutations.

Bassani-Sternberg, Michal / Harari, Alexandre

2022 Volume 40, Issue 7, Page(s) 717–719

Abstract: Immunoediting, the loss of tumor (neo)antigens due to T cell-dependent selection, sculpts tumor immunogenicity. In Nature, Łuksza et al. conceive a model to score neoantigens' immunogenicity and predict tumor clonal evolution. With this model, they ... ...

Abstract	Immunoediting, the loss of tumor (neo)antigens due to T cell-dependent selection, sculpts tumor immunogenicity. In Nature, Łuksza et al. conceive a model to score neoantigens' immunogenicity and predict tumor clonal evolution. With this model, they demonstrate that durable tumor control associates with selective limited acquisition of high-quality mutations.
MeSH term(s)	Antigens, Neoplasm/genetics ; Humans ; Mutation ; Neoplasms/genetics
Chemical Substances	Antigens, Neoplasm
Language	English
Publishing date	2022-07-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2022.06.007
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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Article ; Online: Towards next-generation TIL therapy: TILs enriched in neoepitope-specific T cells.

Arnaud, Marion / Coukos, George / Harari, Alexandre

Clinical and translational medicine

2023 Volume 13, Issue 1, Page(s) e1174

MeSH term(s)	T-Lymphocytes ; Lymphocytes, Tumor-Infiltrating ; Immunotherapy, Adoptive
Language	English
Publishing date	2023-01-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1174
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Article: Vaccines as Priming Tools for T Cell Therapy for Epithelial Cancers.

Kandalaft, Lana E / Harari, Alexandre

Cancers

2021 Volume 13, Issue 22

Abstract: Impressive progress has recently been made in the field of cancer immunotherapy with the adoptive transfer of T cells, a successful personalized strategy, and checkpoint inhibitors (CPI) having extended the survival of numerous patients. However, not all ...

Abstract	Impressive progress has recently been made in the field of cancer immunotherapy with the adoptive transfer of T cells, a successful personalized strategy, and checkpoint inhibitors (CPI) having extended the survival of numerous patients. However, not all patients have been able to benefit from these innovations. A key determinant of the responsiveness to cancer immunotherapies is the presence of T cells within the tumors. These tumor-infiltrating lymphocytes (TILs) are crucial in controlling tumor growth and their activity is being potentiated by immunotherapies. Although some epithelial cancers are associated with spontaneous T-cell and B-cell responses, which makes them good candidates for immunotherapies, it remains to create strategies that would promote lymphocyte infiltration and enable sustained immune responses in immune-resistant tumors. Therapeutic cancer vaccines hold the potential of being able to render "cold", poorly infiltrated tumors into "hot" tumors that would be receptive to cellular immunotherapies. In this review, we elaborate on the obstacles that need to be overcome and the strategies that are being explored to that end, including various types of antigen repertoires and different vaccine platforms and combinations with other available treatments.
Language	English
Publishing date	2021-11-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13225819
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Article ; Online: Deep learning predictions of TCR-epitope interactions reveal epitope-specific chains in dual alpha T cells.

Croce, Giancarlo / Bobisse, Sara / Moreno, Dana Léa / Schmidt, Julien / Guillame, Philippe / Harari, Alexandre / Gfeller, David

Nature communications

2024 Volume 15, Issue 1, Page(s) 3211

Abstract: T cells have the ability to eliminate infected and cancer cells and play an essential role in cancer immunotherapy. T cell activation is elicited by the binding of the T cell receptor (TCR) to epitopes displayed on MHC molecules, and the TCR specificity ... ...

Abstract	T cells have the ability to eliminate infected and cancer cells and play an essential role in cancer immunotherapy. T cell activation is elicited by the binding of the T cell receptor (TCR) to epitopes displayed on MHC molecules, and the TCR specificity is determined by the sequence of its α and β chains. Here, we collect and curate a dataset of 17,715 αβTCRs interacting with dozens of class I and class II epitopes. We use this curated data to develop MixTCRpred, an epitope-specific TCR-epitope interaction predictor. MixTCRpred accurately predicts TCRs recognizing several viral and cancer epitopes. MixTCRpred further provides a useful quality control tool for multiplexed single-cell TCR sequencing assays of epitope-specific T cells and pinpoints a substantial fraction of putative contaminants in public databases. Analysis of epitope-specific dual α T cells demonstrates that MixTCRpred can identify α chains mediating epitope recognition. Applying MixTCRpred to TCR repertoires from COVID-19 patients reveals enrichment of clonotypes predicted to bind an immunodominant SARS-CoV-2 epitope. Overall, MixTCRpred provides a robust tool to predict TCRs interacting with specific epitopes and interpret TCR-sequencing data from both bulk and epitope-specific T cells.
MeSH term(s)	Humans ; T-Lymphocytes ; Epitopes ; Deep Learning ; Immunodominant Epitopes ; COVID-19
Chemical Substances	Epitopes ; Immunodominant Epitopes
Language	English
Publishing date	2024-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47461-8
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Article ; Online: The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients.

Arnaud, Marion / Bobisse, Sara / Chiffelle, Johanna / Harari, Alexandre

Frontiers in immunology

2021 Volume 12, Page(s) 701636

Abstract: Mutation-derived neoantigens are now established as attractive targets for cancer immunotherapy. The field of adoptive T cell transfer (ACT) therapy was significantly reshaped by tumor neoantigens and is now moving towards the genetic engineering of T ... ...

Abstract	Mutation-derived neoantigens are now established as attractive targets for cancer immunotherapy. The field of adoptive T cell transfer (ACT) therapy was significantly reshaped by tumor neoantigens and is now moving towards the genetic engineering of T cells with neoantigen-specific T cell receptors (TCRs). Yet, the identification of neoantigen-reactive TCRs remains challenging and the process needs to be adapted to clinical timelines. In addition, the state of recipient T cells for TCR transduction is critical and can affect TCR-ACT efficacy. Here we provide an overview of the main strategies for TCR-engineering, describe the selection and expansion of optimal carrier cells for TCR-ACT and discuss the next-generation methods for rapid identification of relevant TCR candidates for gene transfer therapy.
MeSH term(s)	Antigens, Neoplasm/immunology ; Humans ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/immunology
Chemical Substances	Antigens, Neoplasm ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2021-07-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.701636
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Article ; Online: Neoantigen-Specific Adoptive Cell Therapies for Cancer: Making T-Cell Products More Personal.

Bianchi, Valentina / Harari, Alexandre / Coukos, George

Frontiers in immunology

2020 Volume 11, Page(s) 1215

Abstract: Mutation-derived neoantigens are taking central stage as a determinant in eliciting effective antitumor immune responses following adoptive T-cell therapies. These mutations are patient-specific, and their targeting calls for highly personalized ... ...

Abstract	Mutation-derived neoantigens are taking central stage as a determinant in eliciting effective antitumor immune responses following adoptive T-cell therapies. These mutations are patient-specific, and their targeting calls for highly personalized pipelines. The promising clinical outcomes of tumor-infiltrating lymphocyte (TIL) therapy have spurred interest in generating T-cell infusion products that have been selectively enriched in neoantigen (or autologous tumor) reactivity. The implementation of an isolation step, prior to T-cell
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Biomarkers ; Cells, Cultured ; Clinical Studies as Topic ; Coculture Techniques ; Cytokines/metabolism ; Epitopes, T-Lymphocyte/immunology ; HLA Antigens/immunology ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocyte Activation/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Precision Medicine/methods ; Protein Binding ; T-Cell Antigen Receptor Specificity ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome
Chemical Substances	Antigens, Neoplasm ; Biomarkers ; Cytokines ; Epitopes, T-Lymphocyte ; HLA Antigens
Language	English
Publishing date	2020-06-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01215
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Article ; Online: Improved predictions of antigen presentation and TCR recognition with MixMHCpred2.2 and PRIME2.0 reveal potent SARS-CoV-2 CD8

Gfeller, David / Schmidt, Julien / Croce, Giancarlo / Guillaume, Philippe / Bobisse, Sara / Genolet, Raphael / Queiroz, Lise / Cesbron, Julien / Racle, Julien / Harari, Alexandre

Cell systems

2023 Volume 14, Issue 1, Page(s) 72–83.e5

Abstract: The recognition of pathogen or cancer-specific epitopes by ... ...

Abstract	The recognition of pathogen or cancer-specific epitopes by CD8
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; Epitopes, T-Lymphocyte ; Antigen Presentation ; SARS-CoV-2 ; Ligands ; COVID-19 ; Receptors, Antigen, T-Cell ; HLA Antigens
Chemical Substances	Epitopes, T-Lymphocyte ; Ligands ; Receptors, Antigen, T-Cell ; HLA Antigens
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2022.12.002
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Article ; Online: Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure.

Vigano, Selena / Bobisse, Sara / Coukos, George / Perreau, Matthieu / Harari, Alexandre

Frontiers in immunology

2020 Volume 11, Page(s) 1350

Abstract: The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can ... ...

Abstract	The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge.
MeSH term(s)	Clonal Anergy/immunology ; HIV Infections/immunology ; Humans ; Neoplasms/immunology ; T-Lymphocytes/immunology
Language	English
Publishing date	2020-06-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01350
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Article ; Online: Antitumour dendritic cell vaccination in a priming and boosting approach.

Harari, Alexandre / Graciotti, Michele / Bassani-Sternberg, Michal / Kandalaft, Lana E

Nature reviews. Drug discovery

2020 Volume 19, Issue 9, Page(s) 635–652

Abstract: Mobilizing antitumour immunity through vaccination potentially constitutes a powerful anticancer strategy but has not yet provided robust clinical benefits in large patient populations. Although major hurdles still exist, we believe that currently ... ...

Abstract	Mobilizing antitumour immunity through vaccination potentially constitutes a powerful anticancer strategy but has not yet provided robust clinical benefits in large patient populations. Although major hurdles still exist, we believe that currently available strategies for vaccines that target dendritic cells or use them to present antitumour antigens could be integrated into existing clinical practice using prime-boost approaches. In the priming phase, these approaches capitalize on either standard treatment modalities to trigger in situ vaccination and release tumour antigens or vaccination with dendritic cells loaded with tumour lysates or patient-specific neoantigens. In a second boost phase, personalized synthetic vaccines specifically boost T cells that were triggered during the priming phase. This immunotherapy approach has been enabled by the substantial recent improvements in dendritic cell vaccines. In this Perspective, we discuss these improvements, highlight how the prime-boost approach can be translated into clinical practice and provide solutions for various anticipated hurdles.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Cancer Vaccines/immunology ; Dendritic Cells/immunology ; Humans ; Immunity/immunology ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes/immunology ; Vaccination/methods
Chemical Substances	Antigens, Neoplasm ; Cancer Vaccines
Language	English
Publishing date	2020-08-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-020-0074-8
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Zs.A 5564: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 334: Show issues
Zs.MG 63: Show issues

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Article: Microfluidic Device for Droplet Pairing by Combining Droplet Railing and Floating Trap Arrays.

Duchamp, Margaux / Arnaud, Marion / Bobisse, Sara / Coukos, George / Harari, Alexandre / Renaud, Philippe

Micromachines

2021 Volume 12, Issue 9

Abstract: Droplet microfluidics are characterized by the generation and manipulation of discrete volumes of solutions, generated with the use of immiscible phases. Those droplets can then be controlled, transported, analyzed or their content modified. In this wide ...

Abstract	Droplet microfluidics are characterized by the generation and manipulation of discrete volumes of solutions, generated with the use of immiscible phases. Those droplets can then be controlled, transported, analyzed or their content modified. In this wide droplet microfluidic toolbox, no means are available to generate, in a controlled manner, droplets co-encapsulating to aqueous phases. Indeed, current methods rely on random co-encapsulation of two aqueous phases during droplet generation or the merging of two random droplets containing different aqueous phases. In this study, we present a novel droplet microfluidic device to reliably and efficiently co-encapsulate two different aqueous phases in micro-droplets. In order to achieve this, we combined existing droplet microfluidic modules in a novel way. The different aqueous phases are individually encapsulated in droplets of different sizes. Those droplet populations are then filtered in order to position each droplet type towards its adequate trapping compartment in traps of a floating trap array. Single droplets, each containing a different aqueous phase, are thus paired and then merged. This pairing at high efficiency is achieved thanks to a unique combination of floating trap arrays, a droplet railing system and a droplet size-based filtering mechanism. The microfluidic chip design presented here provides a filtering threshold with droplets larger than 35 μm (big droplets) being deviated to the lower rail while droplets smaller than 20 μm (small droplets) remain on the upper rail. The effects of the rail height and the distance between the two (upper and lower) rails were investigated. The optimal trap dimensions provide a trapping efficiency of 100% for small and big droplets with a limited double trapping (both compartments of the traps filled with the same droplet type) of 5%. The use of electrocoalescence enables the generation of a droplet while co-encapsulating two aqueous phases. Using the presented microfluidic device libraries of 300 droplets, dual aqueous content can be generated in less than 30 min.
Language	English
Publishing date	2021-09-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2620864-7
ISSN	2072-666X
ISSN	2072-666X
DOI	10.3390/mi12091076
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