# The Interplay Between PD-1 Blockade and T cell Development in the Context of Thymic Regeneration in Prostate Cancer

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Immunotherapies, such as PD-1 blockade, have shown therapeutic potential in prostate cancer; however, only
a portion of patients respond, suggesting unidentified mechanisms of resistance. The current standard of care
for prostate cancer is androgen deprivation therapy (ADT), which targets hormone-sensitive tumor cells.
Interestingly, ADT also results in regeneration of the thymus and increased thymic output of newly developed T
cells. We have shown that newly generated T cells resulting from ADT-induced thymic regeneration traffic to
tumors where they can contribute to the tumor immune milieu. Further, PD-1 deficiency or blockade leads to an
increase in the generation of thymic regulatory T cells (Tregs), suggesting that PD-1 regulates the selection of
these cells in the thymus and, therefore, the Treg repertoire. It is unclear whether PD-1 limits Treg development
by inhibiting the T cell receptor signaling pathway or the CD28 costimulatory pathway, but it has already been
established that CD28 is critical for Treg development. Based upon these data, I hypothesize that inhibition
of PD-1 could broaden the repertoire of Tregs available to traffic to prostate tumors and PD-1 limits Treg
selection through inhibition of CD28 signaling. First, I will identify changes in tumor infiltrating Treg repertoire
resulting from PD-1 blockade in the context of thymic regeneration. A castration model of ADT is used to induce
thymic regeneration in a castration and immunotherapy resistant murine model of prostate cancer. Animals are
treated with aPD-1 or control and the T cell repertoire is examined. Additionally, I will examine pre- and post-
treatment samples collected as a part of an ongoing clinical trial where treatment-naïve men diagnosed with
advanced prostate cancer receive ADT in combination with aPD-1, allowing us to perform real-time evaluation
of the impact of PD-1 blockade during thymic regeneration on repertoire selection in patients . Second, I will
determine the mechanism by which PD-1 limits Treg development. This will be accomplished through the use of
the CRISPR-Cas9 system to mutate motifs in the CD28 cytoplasmic tail that are sites of PD-1 inhibition to
determine dependence on CD28 signaling. Further, alterations of downstream signaling pathways resulting from
PD-1 deficiency will be examined by transcriptomic and proteomic studies. The outcomes of this proposal are
anticipated to reveal the how PD-1 blockade impacts the immune repertoire in the context of ADT-induced thymic
regeneration to identify potential mechanisms of immunotherapy resistance in prostate cancer. These studies
may also lead to new justifications for combination therapies in prostate cancer to increase the number of patients
responding to checkpoint blockade.

## Key facts

- **NIH application ID:** 10370320
- **Project number:** 5F31CA261058-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Breanna Caruso
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370320

## Citation

> US National Institutes of Health, RePORTER application 10370320, The Interplay Between PD-1 Blockade and T cell Development in the Context of Thymic Regeneration in Prostate Cancer (5F31CA261058-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370320. Licensed CC0.

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