Molecular Characterization of Autoreactive B Cells in Immune Checkpoint Inhibitor-Induced Autoimmune Sicca

免疫检查点抑制剂诱导的自身免疫性干燥症中自身反应性 B 细胞的分子特征

• 批准号: 10427436
• 负责人: Rachel H Bonami
• 金额: $ 8.65万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427436
• 关键词: Activities of Daily Living; Acute; Affinity; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B lymphocyte immortalization; B-Cell Antigen Receptor; B-Cell Receptor Binding; B-Lymphocyte Subsets; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Biological Markers; Blood specimen; Cancer Patient; Cell surface; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clonal Evolution; Clone Cells; Collaborations; Communities; Computerized Medical Record; Data; Data Set; Databases; Development; Diagnostic; Disease; Doctor of Medicine; Exhibits; Female; Frequencies; Future; Genes; Genetic Transcription; Human; Hybridomas; Immune Tolerance; Immune checkpoint inhibitor; Immune system; Immunosuppression; Individual; Insulin-Dependent Diabetes Mellitus; Investigation; Knowledge; Letters; Memory; Molecular; Monoclonal Antibodies; Mutate; Mutation; Nature; Oncologist; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phylogenetic Analysis; Plasmablast; Play; Prednisone; Production; Receptor Gene; Research; Risk; Role; Shapes; Sjogren' s Syndrome; Symptoms; Syndrome; T cell response; T-Lymphocyte; Technology; Trees; Work; autoimmune pathogenesis; autoreactive B cell; autoreactivity; beta diversity; biobank; cancer therapy; checkpoint therapy; design; experimental analysis; experimental study; immune-related adverse events; improved; insight; man; melanoma; new technology; peripheral blood; phenotypic biomarker; phenotypic data; programs; recruit; response; rituximab; searchable database; specific biomarkers; tool; transcriptome sequencing; transcriptomics; treatment response; tumor

PROJECT SUMMARY Autoimmune sicca can arise spontaneously, as in Sjӧgren’s syndrome (SjS), or acutely, as an immune-related adverse event (irAE) following immune checkpoint inhibitor (ICI) therapy for cancer. Of the approximately 500,000 patients treated with ICIs annually, an estimated 3-24% develop new-onset sicca symptoms; these numbers will increase as FDA approvals for ICI use broaden. We define ICI-induced autoimmune sicca (ICIA- sicca) as the 10-25% of ICI-sicca patients who develop demonstrable B cell autoimmunity, as shown by Ro52 or Ro60 autoantibodies. New, specific biomarkers are needed to predict who will develop which types of irAEs. The “experiment of man” in ICIA-sicca enables comparison of B cells before and after Ro autoimmunity develops, in contrast to the SjS “experiment of nature”, in which the initiation point of autoimmunity is not known. B cell clones arise via T cell selection and B cell receptor (BCR) affinity maturation in SjS, but it is unknown whether such highly focused B cell responses result from ICI use in ICIA-sicca, or which functional B cell subsets (e.g. memory) are expanded. To fill these gaps in knowledge, we built a carefully curated biobank of peripheral blood samples collected from patients before ICI therapy and following ICIA-sicca development in collaboration with Doug Johnson, M.D., M.S.C.I., Vanderbilt Melanoma Research Program Director and irAE expert. High-throughput human hybridoma technology will be used in Aim 1 to identify the molecular features of BCRs expressed by Ro52 and Ro60-binding B cells. We will discern the role that mutation and selection plays in autoreactive B cell expansion that precedes autoantibody production. Peripheral blood expansion of CD21lo B cells (an autoreactive-prone subset) is observed in SjS patients and predicts irAEs in ICI-treated patients. We will therefore investigate expansion of this and other B cell subsets in Aim 2 by comparing single- cell repertoire (BCRseq), phenotypic (CITEseq), and transcriptomic (RNAseq) B cell signatures in ICIA-sicca patients before ICI treatment and following ICIA-sicca development. We will use these data to identify hallmarks of expanded B cell clones and subsets in ICIA-sicca. We will further integrate Aim 1 and Aim 2 data to determine Ro52/Ro60-specific V gene identity, clonal relatedness, and phenotypic information to infer the functional capacity and developmental origins of B cells that recognize SjS-associated autoantigens in ICIA- sicca. Autoreactive B cells that recognize other autoantigens in ICIA-sicca will be identified by the unbiased approach in Aim 2. These studies will uncover specific sequence and phenotypic biomarkers that can be used in the future to predict impending ICIA-sicca and assess immunosuppressive efficacy in ICIA-sicca. Human Ro52 and Ro60 monoclonal antibodies, the autoreactive BCR motif database, and the parallel BCRseq/CITEseq/RNAseq data we will generate will be made publicly available to support irAE and spontaneous autoimmune disease research. The experimental and analysis blueprints we will create will set the stage for future studies to investigate the origins of other irAEs following ICI treatment.

项目总结