# Mechanisms of Thyroid Autoimmunity in Checkpoint Immunotherapy

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $175,392

## Abstract

PROJECT SUMMARY
 Proposed is a five-year research career development plan focused on evaluating the mechanisms of
thyroid autoimmunity during cancer immunotherapy. The candidate, Dr. Melissa G. Lechner, M.D., Ph.D., is an
Assistant Professor of Medicine in Endocrinology at the University of California, Los Angeles (UCLA). This
proposal builds upon her strong background and provides new training in mouse models of autoimmunity,
advanced transcriptomic and proteomic techniques, and bioinformatics. During the award term, Dr. Lechner will
be mentored by Dr. Maureen Su, M.D., a leader in the field of autoimmune disease and experienced physician
scientist with a track record of mentoring more than 30 students, post-doctoral fellows, and junior faculty. She
will have additional support from co-mentor Dr. Greg Brent, M.D., a renowned thyroid researcher, and a strong
team of advisors with technical and content expertise.
 Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer treatment, but their use is limited
by the development of unwanted autoimmune side effects seen in up to 60% of patients. These immune-related
adverse events (IrAE) interrupt cancer treatment and lead to organ dysfunction, hospitalization, and even death.
The cause of IrAEs remains unknown, however, recent data suggest that toxicity can be uncoupled from anti-
tumor effects. Thyroiditis, a common IrAE, is ideal for studying mechanisms of IrAE development because of the
ability to directly sample immune infiltrates in the thyroid by fine needle biopsy and to compare with Hashimoto’s
thyroiditis (HT), a well-described spontaneous thyroid autoimmune disease. Interestingly, ICI-thyroiditis has both
similar and distinct features from HT. Dr. Lechner developed a mouse model that recapitulates human IrAEs
from checkpoint immunotherapy, including multi-organ immune infiltrates and autoantibodies. Using this model,
she has identified a role for RORg+ Th17 and Tc17 cells and T peripheral helper (TPH, CXCR5-ICOS+PD1+) cells
in IrAEs. These cell populations have previously been associated with spontaneous autoimmune diseases,
including HT, but not yet IrAE. Additionally, studies in patients with checkpoint-inhibitor thyroiditis showed
intrathyroidal T cell accumulation and increased RORg+ T cells. Therefore, in Specific Aim 1, Dr. Lechner will
determine the role of RORg+ Th17 and Tc17 and TPH cells in IrAE development using a mouse model and analysis
of thyroid-infiltrating cells patients with ICI-thyroiditis vs. HT. The absence of autoantibodies to known thyroid
antigens (e.g. thyroid peroxidase thyroglobulin) in many ICI-thyroiditis patients also suggests immune attack
against yet unidentified targets. Thus, in Specific Aim 2, Dr. Lechner will identify the antigen targets in ICI
thyroiditis, evaluate immune responses to these antigens, and compare them known antigens in HT. With this
work, Dr. Lechner aims to advance our understanding of mechanisms underlying thyroid autoimmune...

## Key facts

- **NIH application ID:** 10454346
- **Project number:** 5K08DK129829-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Melissa G Lechner
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $175,392
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454346

## Citation

> US National Institutes of Health, RePORTER application 10454346, Mechanisms of Thyroid Autoimmunity in Checkpoint Immunotherapy (5K08DK129829-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10454346. Licensed CC0.

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