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Article ; Online: The Unexpected Benefit of TCR Cross-Reactivity in Cancer Immunotherapy.

Bieberich, Florian / Reddy, Sai T

2023 Volume 83, Issue 19, Page(s) 3168–3169

Abstract: The ability of T-cell receptors (TCR) to recognize tumor-associated antigens (TAA) is a key driver of adoptive transfer of tumor-infiltrating lymphocyte (TIL) T cells, which can be a highly effective cancer immunotherapy. While it is common knowledge ... ...

Abstract	The ability of T-cell receptors (TCR) to recognize tumor-associated antigens (TAA) is a key driver of adoptive transfer of tumor-infiltrating lymphocyte (TIL) T cells, which can be a highly effective cancer immunotherapy. While it is common knowledge that TCRs are cross-reactive and can bind multiple different peptide antigens, this is typically considered an unattractive feature and limitation for TCR-based therapies. In a recent publication in Cell, Dolton and colleagues discover that certain TCRs, isolated from TILs used for successful treatment of melanoma, possess beneficial cross-reactivity by recognizing multiple TAA. Moreover, they elucidate the cumulative value of TCR cross-reactivity on cancer cell eradication and its prospective advantages for targeted cancer immunotherapies.
MeSH term(s)	Humans ; Prospective Studies ; Receptors, Antigen, T-Cell ; T-Lymphocytes ; Lymphocytes, Tumor-Infiltrating ; Antigens, Neoplasm ; Immunotherapy ; Melanoma/therapy ; Immunotherapy, Adoptive
Chemical Substances	Receptors, Antigen, T-Cell ; Antigens, Neoplasm
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-23-2594
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Article ; Online: speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing.

Castellanos-Rueda, Rocío / Di Roberto, Raphaël B / Bieberich, Florian / Schlatter, Fabrice S / Palianina, Darya / Nguyen, Oanh T P / Kapetanovic, Edo / Läubli, Heinz / Hierlemann, Andreas / Khanna, Nina / Reddy, Sai T

Nature communications

2022 Volume 13, Issue 1, Page(s) 6555

Abstract: Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only ... ...

Abstract	Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an integrated method for engineering CAR T cells via signaling domain shuffling and pooled functional screening. Leveraging the inherent modularity of natural signaling domains, we generate a library of 180 unique CAR variants genomically integrated into primary human T cells by CRISPR-Cas9. In vitro tumor cell co-culture, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), enables high-throughput screening for identifying several variants with tumor killing properties and T cell phenotypes markedly different from standard CARs. Mapping of the CAR scRNA-seq data onto that of tumor infiltrating lymphocytes further helps guide the selection of variants. These results thus help expand the CAR signaling domain combination space, and supports speedingCARs as a tool for the engineering of CARs for potential therapeutic development.
MeSH term(s)	Humans ; Receptors, Chimeric Antigen/genetics ; T-Lymphocytes ; Signal Transduction ; Lymphocyte Activation ; Neoplasms ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-11-02
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/s41467-022-34141-8
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Article ; Online: High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity.

Vazquez-Lombardi, Rodrigo / Jung, Johanna S / Schlatter, Fabrice S / Mei, Anna / Mantuano, Natalia Rodrigues / Bieberich, Florian / Hong, Kai-Lin / Kucharczyk, Jakub / Kapetanovic, Edo / Aznauryan, Erik / Weber, Cédric R / Zippelius, Alfred / Läubli, Heinz / Reddy, Sai T

Immunity

2022 Volume 55, Issue 10, Page(s) 1953–1966.e10

Abstract: A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of ... ...

Abstract	A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications.
MeSH term(s)	Antigens, Neoplasm ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Peptides ; Receptors, Antigen, T-Cell
Chemical Substances	Antigens, Neoplasm ; Peptides ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.09.004
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Article ; Online: speedingCARs

Rocío Castellanos-Rueda / Raphaël B. Di Roberto / Florian Bieberich / Fabrice S. Schlatter / Darya Palianina / Oanh T. P. Nguyen / Edo Kapetanovic / Heinz Läubli / Andreas Hierlemann / Nina Khanna / Sai T. Reddy

Nature Communications, Vol 13, Iss 1, Pp 1-

accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing

2022 Volume 16

Abstract: Chimeric antigen receptors (CAR) are a promising option for cell-based immunotherapy for cancer and other immune diseases. Here the authors develop speedingCARs, an integrated CAR design and screening platform based on modular signaling domain shuffling ... ...

Abstract	Chimeric antigen receptors (CAR) are a promising option for cell-based immunotherapy for cancer and other immune diseases. Here the authors develop speedingCARs, an integrated CAR design and screening platform based on modular signaling domain shuffling and single cell transcriptomic analyses, and test its potential for identifying and validating novel CAR designs.
Keywords	Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Platypus: an open-access software for integrating lymphocyte single-cell immune repertoires with transcriptomes.

Yermanos, Alexander / Agrafiotis, Andreas / Kuhn, Raphael / Robbiani, Damiano / Yates, Josephine / Papadopoulou, Chrysa / Han, Jiami / Sandu, Ioana / Weber, Cédric / Bieberich, Florian / Vazquez-Lombardi, Rodrigo / Dounas, Andreas / Neumeier, Daniel / Oxenius, Annette / Reddy, Sai T

NAR genomics and bioinformatics

2021 Volume 3, Issue 2, Page(s) lqab023

Abstract: High-throughput single-cell sequencing (scSeq) technologies are revolutionizing the ability to molecularly profile B and T lymphocytes by offering the opportunity to simultaneously obtain information on adaptive immune receptor repertoires (VDJ ... ...

Abstract	High-throughput single-cell sequencing (scSeq) technologies are revolutionizing the ability to molecularly profile B and T lymphocytes by offering the opportunity to simultaneously obtain information on adaptive immune receptor repertoires (VDJ repertoires) and transcriptomes. An integrated quantification of immune repertoire parameters, such as germline gene usage, clonal expansion, somatic hypermutation and transcriptional states opens up new possibilities for the high-resolution analysis of lymphocytes and the inference of antigen-specificity. While multiple tools now exist to investigate gene expression profiles from scSeq of transcriptomes, there is a lack of software dedicated to single-cell immune repertoires. Here, we present Platypus, an open-source software platform providing a user-friendly interface to investigate B-cell receptor and T-cell receptor repertoires from scSeq experiments. Platypus provides a framework to automate and ease the analysis of single-cell immune repertoires while also incorporating transcriptional information involving unsupervised clustering, gene expression and gene ontology. To showcase the capabilities of Platypus, we use it to analyze and visualize single-cell immune repertoires and transcriptomes from B and T cells from convalescent COVID-19 patients, revealing unique insight into the repertoire features and transcriptional profiles of clonally expanded lymphocytes. Platypus will expedite progress by facilitating the analysis of single-cell immune repertoire and transcriptome sequencing.
Language	English
Publishing date	2021-04-14
Publishing country	England
Document type	Journal Article
ISSN	2631-9268
ISSN (online)	2631-9268
DOI	10.1093/nargab/lqab023
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Single-Cell Atlas of Lymphocyte Adaptive Immune Repertoires and Transcriptomes Reveals Age-Related Differences in Convalescent COVID-19 Patients.

Bieberich, Florian / Vazquez-Lombardi, Rodrigo / Yermanos, Alexander / Ehling, Roy A / Mason, Derek M / Wagner, Bastian / Kapetanovic, Edo / Di Roberto, Raphael Brisset / Weber, Cédric R / Savic, Miodrag / Rudolf, Fabian / Reddy, Sai T

Frontiers in immunology

2021 Volume 12, Page(s) 701085

Abstract: COVID-19 disease outcome is highly dependent on adaptive immunity from T and B lymphocytes, which play a critical role in the control, clearance and long-term protection against SARS-CoV-2. To date, there is limited knowledge on the composition of the T ... ...

Abstract	COVID-19 disease outcome is highly dependent on adaptive immunity from T and B lymphocytes, which play a critical role in the control, clearance and long-term protection against SARS-CoV-2. To date, there is limited knowledge on the composition of the T and B cell immune receptor repertoires [T cell receptors (TCRs) and B cell receptors (BCRs)] and transcriptomes in convalescent COVID-19 patients of different age groups. Here, we utilize single-cell sequencing (scSeq) of lymphocyte immune repertoires and transcriptomes to quantitatively profile the adaptive immune response in COVID-19 patients of varying age. We discovered highly expanded T and B cells in multiple patients, with the most expanded clonotypes coming from the effector CD8
MeSH term(s)	Adaptive Immunity ; Adult ; Aged ; Aging/immunology ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; COVID-19/immunology ; Cells, Cultured ; Convalescence ; Female ; Humans ; Male ; Middle Aged ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, T-Cell/genetics ; SARS-CoV-2/physiology ; Single-Cell Analysis ; Transcriptome ; Young Adult
Chemical Substances	Receptors, Antigen, B-Cell ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2021-07-12
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.701085
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Locus-specific expression of transposable elements in single cells with CELLO-seq.

Berrens, Rebecca V / Yang, Andrian / Laumer, Christopher E / Lun, Aaron T L / Bieberich, Florian / Law, Cheuk-Ting / Lan, Guocheng / Imaz, Maria / Bowness, Joseph S / Brockdorff, Neil / Gaffney, Daniel J / Marioni, John C

Nature biotechnology

2021 Volume 40, Issue 4, Page(s) 546–554

Abstract: Transposable elements (TEs) regulate diverse biological processes, from early development to cancer. Expression of young TEs is difficult to measure with next-generation, single-cell sequencing technologies because their highly repetitive nature means ... ...

Abstract	Transposable elements (TEs) regulate diverse biological processes, from early development to cancer. Expression of young TEs is difficult to measure with next-generation, single-cell sequencing technologies because their highly repetitive nature means that short complementary DNA reads cannot be unambiguously mapped to a specific locus. Single CELl LOng-read RNA-sequencing (CELLO-seq) combines long-read single cell RNA-sequencing with computational analyses to measure TE expression at unique loci. We used CELLO-seq to assess the widespread expression of TEs in two-cell mouse blastomeres as well as in human induced pluripotent stem cells. Across both species, old and young TEs showed evidence of locus-specific expression with simulations demonstrating that only a small number of very young elements in the mouse could not be mapped back to the reference with high confidence. Exploring the relationship between the expression of individual elements and putative regulators revealed large heterogeneity, with TEs within a class showing different patterns of correlation and suggesting distinct regulatory mechanisms.
MeSH term(s)	Animals ; DNA Transposable Elements/genetics ; Humans ; Induced Pluripotent Stem Cells ; Mice ; RNA
Chemical Substances	DNA Transposable Elements ; RNA (63231-63-0)
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-021-01093-1
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Article ; Online: A single-cell atlas of lymphocyte adaptive immune repertoires and transcriptomes reveals age-related differences in convalescent COVID-19 patients

Bieberich, Florian / Vazquez-Lombardi, Rodrigo / Yermanos, Alexander / Ehling, Roy A / Wagner, Bastian / Kapetanovic, Edo / Di Roberto, Raphael Brisset / Savic, Miodrag / Rudolf, Fabian / Reddy, Sai T

bioRxiv

Abstract	COVID-19 disease outcome is highly dependent on adaptive immunity from T and B lymphocytes, which play a critical role in the control, clearance and long-term protection against SARS-CoV-2. To date, there is limited knowledge on the composition of the T and B cell immune receptor repertoires [T cell receptors (TCRs) and B cell receptors (BCRs)] and transcriptomes in convalescent COVID-19 patients of different age groups. Here, we utilize single-cell sequencing (scSeq) of lymphocyte immune repertoires and transcriptomes to quantitatively profile the adaptive immune response in COVID-19 patients of varying age. We discovered highly expanded T and B cells in multiple patients, with the most expanded clonotypes coming from the effector CD8+ T cell population. Highly expanded CD8+ and CD4+ T cell clones show elevated markers of cytotoxicity (CD8: PRF1, GZMH, GNLY; CD4: GZMA), whereas clonally expanded B cells show markers of transition into the plasma cell state and activation across patients. By comparing young and old convalescent COVID-19 patients (mean ages = 31 and 66.8 years, respectively), we found that clonally expanded B cells in young patients were predominantly of the IgA isotype and their BCRs had incurred higher levels of somatic hypermutation than elderly patients. In conclusion, our scSeq analysis defines the adaptive immune repertoire and transcriptome in convalescent COVID-19 patients and shows important age-related differences implicated in immunity against SARS-CoV-2.
Keywords	covid19
Language	English
Publishing date	2021-02-12
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.02.12.430907
Database	COVID19

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Article ; Online: A single-cell atlas of lymphocyte adaptive immune repertoires and transcriptomes reveals age-related differences in convalescent COVID-19 patients

Bieberich, Florian / Vazquez-Lombardi, Rodrigo / Yermanos, Alexander / Ehling, Roy A / Mason, Derek M / Wagner, Bastian / Kapetanovic, Edo / Di Roberto, Raphael Brisset / Weber, Cedric R / Savic, Miodrag / Rudolf, Fabian / Reddy, Sai T

bioRxiv

Abstract	COVID-19 disease outcome is highly dependent on adaptive immunity from T and B lymphocytes, which play a critical role in the control, clearance and long-term protection against SARS-CoV-2. To date, there is limited knowledge on the composition of the T and B cell immune receptor repertoires [T cell receptors (TCRs) and B cell receptors (BCRs)] and transcriptomes in convalescent COVID-19 patients of different age groups. Here, we utilize single-cell sequencing (scSeq) of lymphocyte immune repertoires and transcriptomes to quantitatively profile the adaptive immune response in COVID-19 patients of varying age. We discovered highly expanded T and B cells in multiple patients, with the most expanded clonotypes coming from the effector CD8+ T cell population. Highly expanded CD8+ and CD4+ T cell clones show elevated markers of cytotoxicity (CD8: PRF1, GZMH, GNLY; CD4: GZMA), whereas clonally expanded B cells show markers of transition into the plasma cell state and activation across patients. By comparing young and old convalescent COVID-19 patients (mean ages = 31 and 66.8 years, respectively), we found that clonally expanded B cells in young patients were predominantly of the IgA isotype and their BCRs had incurred higher levels of somatic hypermutation than elderly patients. In conclusion, our scSeq analysis defines the adaptive immune repertoire and transcriptome in convalescent COVID-19 patients and shows important age-related differences implicated in immunity against SARS-CoV-2.
Keywords	covid19
Language	English
Publishing date	2021-02-15
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.02.12.430907
Database	COVID19

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Article ; Online: SARS-CoV-2 reactive and neutralizing antibodies discovered by single-cell sequencing of plasma cells and mammalian display.

Cell reports

2021 Volume 38, Issue 3, Page(s) 110242

Abstract: Characterization of COVID-19 antibodies has largely focused on memory B cells; however, it is the antibody-secreting plasma cells that are directly responsible for the production of serum antibodies, which play a critical role in resolving SARS-CoV-2 ... ...

Abstract	Characterization of COVID-19 antibodies has largely focused on memory B cells; however, it is the antibody-secreting plasma cells that are directly responsible for the production of serum antibodies, which play a critical role in resolving SARS-CoV-2 infection. Little is known about the specificity of plasma cells, largely because plasma cells lack surface antibody expression, thereby complicating their screening. Here, we describe a technology pipeline that integrates single-cell antibody repertoire sequencing and mammalian display to interrogate the specificity of plasma cells from 16 convalescent patients. Single-cell sequencing allows us to profile antibody repertoire features and identify expanded clonal lineages. Mammalian display screening is used to reveal that 43 antibodies (of 132 candidates) derived from expanded plasma cell lineages are specific to SARS-CoV-2 antigens, including antibodies with high affinity to the SARS-CoV-2 receptor-binding domain (RBD) that exhibit potent neutralization and broad binding to the RBD of SARS-CoV-2 variants (of concern/interest).
MeSH term(s)	Animals ; Antibodies, Neutralizing/isolation & purification ; Antibodies, Viral/isolation & purification ; COVID-19/immunology ; COVID-19/prevention & control ; Cells, Cultured ; Cohort Studies ; Gene Library ; HEK293 Cells ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Mammals ; Neutralization Tests ; Peptide Library ; Plasma Cells/chemistry ; Plasma Cells/metabolism ; SARS-CoV-2/immunology ; Single-Cell Analysis/methods
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Peptide Library
Language	English
Publishing date	2021-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.110242
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