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

> **NIH NIH R03** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $86,500

## Abstract

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...

## Key facts

- **NIH application ID:** 10287167
- **Project number:** 1R03AI163835-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Rachel H Bonami
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $86,500
- **Award type:** 1
- **Project period:** 2021-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287167

## Citation

> US National Institutes of Health, RePORTER application 10287167, Molecular Characterization of Autoreactive B Cells in Immune Checkpoint Inhibitor-Induced Autoimmune Sicca (1R03AI163835-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10287167. Licensed CC0.

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