Single-cell RNA sequencing coupled to TCR profiling of large granular lymphocyte leukemia T cells

Gao, Shaojian; Wu, Zhijie; Arnold, Bradley; Diamond, Carrie; Batchu, Sai; Giudice, Valentina; Alemu, Lemlem; Raffo, Diego Quinones; Feng, Xingmin; Barrett, John T.; Ito, Sawa; Young, Neal S.

doi:10.1038/s41467-022-29175-x

Cited by 28 publications

(23 citation statements)

References 48 publications

(92 reference statements)

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“…Concomitantly, the Gini index of T-cell clone size distribution dramatically increased after CAR T-cell infusion, reaching a higher level than HD controls and similar to patients with T-LGLL with obvious T-cell clonal expansion (Figure 2F). 17 Among the 500 T cells with highest CAR expression, we found decreased expression of genes involved in STAT signaling (P < .001) and inflammatory response (P = .03; supplemental Figure 9).…”

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confidence: 83%

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Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

Rejeski

Blumenberg

et al. 2022

Blood

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The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present a case of bone marrow (BM) failure in a 57-year old man with DLBCL-type Richter transformation receiving tisagenlecleucel in a standard-of-care setting. His clinical course was notable for underlying BM infiltration, severe cytokine release syndrome, and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia - including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated migration of CAR T-cells to the BM, as well as peripheral blood expansion of both CAR and non-CAR bearing CD8+CD57+ T-cells, an immunophenotype linked to oligoclonality in aplastic anemia. From single-cell level transcriptomics, this cytotoxic T-cell population was characterized by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathophysiologic mechanism.

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confidence: 83%

“…(F) Gini index of TCR clone size distribution was compared in pretreatment and posttreatment samples and with reported HDs and patients with T-LGLL. 17 (G) Ranking of the top 10 TCR clonotypes from pretreatment and posttreatment samples. Blue lines indicate the top 5 clones before treatment; red lines indicate the top 5 clones after treatment.…”

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confidence: 99%

Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

Rejeski

Blumenberg

et al. 2022

Blood

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“…This method is most commonly used in conjunction with microfluidics-based platforms such as those offered by 10X Genomics, though similar methods have now been developed for compatibility with well-based platforms, including BD Rhapsody and Seq-Well, which use a unique 3' approach to capture TCR sequences [59]. The advent of techniques that allow for simultaneous study of the whole transcriptome and TCR/BCR sequences provides the opportunity to analyze the transcriptomes of cells with specific TCR or BCRs, for example, clonally expanded populations [60][61][62][63][64].…”

Section: Single-cell Tcr/bcr Sequencingmentioning

confidence: 99%

Single-cell RNA-seq methods to interrogate virus-host interactions

et al. 2022

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The twenty-first century has seen the emergence of many epidemic and pandemic viruses, with the most recent being the SARS-CoV-2-driven COVID-19 pandemic. As obligate intracellular parasites, viruses rely on host cells to replicate and produce progeny, resulting in complex virus and host dynamics during an infection. Single-cell RNA sequencing (scRNA-seq), by enabling broad and simultaneous profiling of both host and virus transcripts, represents a powerful technology to unravel the delicate balance between host and virus. In this review, we summarize technological and methodological advances in scRNA-seq and their applications to antiviral immunity. We highlight key scRNA-seq applications that have enabled the understanding of viral genomic and host response heterogeneity, differential responses of infected versus bystander cells, and intercellular communication networks. We expect further development of scRNA-seq technologies and analytical methods, combined with measurements of additional multi-omic modalities and increased availability of publicly accessible scRNA-seq datasets, to enable a better understanding of viral pathogenesis and enhance the development of antiviral therapeutics strategies.

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“…T-cell large granular lymphocytic leukemia (T-LGLL) is a lymph proliferative disease characterized by the clonal expansion of terminal differentiation effector and memory cytotoxic T lymphocytes (CTLs). Abnormalities in cell survival and apoptotic gene programming and significant downregulation of CD8+T cell apoptotic genes are prominent features of T-LGLL cells ( 17 ). The studies on single-cell TCR/BCR sequencing technology applied to tumors are summarized in Table 1 .…”

Section: Tumor Immune Microenvironmentmentioning

confidence: 99%

Research progress on application of single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, and infectious diseases

Shen

Luo

et al. 2022

Front. Immunol.

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Single-cell omics is the profiling of individual cells through sequencing and other technologies including high-throughput analysis for single-cell resolution, cell classification, and identification as well as time series analyses. Unlike multicellular studies, single-cell omics overcomes the problem of cellular heterogeneity. It provides new methods and perspectives for in-depth analyses of the behavior and mechanism of individual cells in the cell population and their relationship with the body, and plays an important role in basic research and precision medicine. Single-cell sequencing technologies mainly include single-cell transcriptome sequencing, single-cell assay for transposase accessible chromatin with high-throughput sequencing, single-cell immune profiling (single-cell T-cell receptor [TCR]/B-cell receptor [BCR] sequencing), and single-cell transcriptomics. Single-cell TCR/BCR sequencing can be used to obtain a large amount of single-cell gene expression and immunomics data at one time, and combined with transcriptome sequencing and TCR/BCR diversity data, can resolve immune cell heterogeneity. This paper summarizes the progress in applying single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, infectious diseases, immunotherapy, and chronic inflammatory diseases, and discusses its shortcomings and prospects for future application.

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Single-cell RNA sequencing coupled to TCR profiling of large granular lymphocyte leukemia T cells

Cited by 28 publications

References 48 publications

Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

Single-cell RNA-seq methods to interrogate virus-host interactions

Research progress on application of single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, and infectious diseases

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