# (8) Mechanisms of autoimmune endocrine diseases in patients receiving checkpoint inhibitors

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $585,633

## Abstract

Summary
Checkpoint inhibitor (CPI) therapy has greatly improved the treatment of cancers that had previously been
considered intractable. As a result of the intended biologic activity of these drugs, which enable activation of T
cells that can cause tumor destruction, new autoimmune adverse events have occurred. Major targets of these
adverse events have been endocrine tissues including thyroid and beta cells in the pancreas. Thyroiditis is
frequent and autoimmune diabetes has emerged as a serious adverse event often requiring intensive care.
The reasons why some individuals develop these autoimmune events and why some are protected are not
known but this information may lead to ways of preventing the occurrence of these adverse events. The overall
objective if this proposal is to understand the molecular and cellular immunologic basis for autoimmune
diabetes and thyroid disease and to test whether they can be prevented with agents that are specific in their
actions. The hypothesis that we wish to test is that in individuals who develop endocrinopathies CPI therapy
induces pathologic T cells, loss of B cell tolerance, and dysfunctional regulatory T cells. Our preliminary data
has identified phenotypic differences in autoantigen reactive effector T cells and Tregs in those who do and do
not develop endocrinopathies. In addition, our analysis of autoreactive B cells suggests that CPI therapy
affects peripheral B cell tolerance checkpoints and results in an increased frequency of autoreactive mature
naïve B cells. We plan to analyze, using Seq-Well single cells in patients who are followed prospectively from
before treatment to when they present with autoimmune endocrinopathies. In the subgroup of individuals who
are HLA-A2 (~40%) we will study thyroid and diabetes reactive CD8+ T cells with cellular libraries and CyTOF
and determine whether the T cell receptors that are found on the antigen reactive cells can be detected prior to
treatment and in which subpopulation. We will also determine whether CPIs affect the number and function of
Tregs and address specifically whether the CPI causes the Tregs to produce pathologic cytokines. We will use
established techniques to determine whether the CPIs induce a failure of peripheral B cell tolerance and
identify the relationship between changes in B cells and Tregs. We will be collecting data on the autoreactive T
and B cell repertoire that we will correlate with clinical responses to the primary tumors. Finally, our studies of
the immunologic mechanisms that underlie these adverse events suggest ways in which they may be
prevented, which we will test in a murine model of anti-PD-L1 induced diabetes in NOD mice. We will test
whether B cell depletion or enhancement of Tregs, either by low doses of IL-2 or by infusion of diabetes
antigen specific Tregs can prevent diabetes onset. These studies therefore, will elucidate the mechanisms of
these serious adverse events, identify individuals who are at greatest r...

## Key facts

- **NIH application ID:** 9929558
- **Project number:** 5R01CA227473-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kevan C Herold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,633
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929558

## Citation

> US National Institutes of Health, RePORTER application 9929558, (8) Mechanisms of autoimmune endocrine diseases in patients receiving checkpoint inhibitors (5R01CA227473-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9929558. Licensed CC0.

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