# PD-1 blockade effects on bone strength and metastatic progression

> **NIH NIH F99** · VANDERBILT UNIVERSITY · 2024 · $35,870

## Abstract

PROJECT SUMMARY
Immune checkpoint inhibitors (ICIs) enable anti-tumor immunity by blocking immunoregulatory receptor-ligand
interactions (e.g., programmed cell death protein 1 [PD-1] and its ligand [PD-L1]). Despite their widespread
success as an anti-cancer therapy, ICIs function poorly in patients with bone metastases, and bone loss
and elevated fracture risk are reported in patients receiving ICI therapy. My preliminary data indicate that
PD-1 global knockout or pharmacologic blockade decreases bone mass in both tumor naïve mice and mice with
bone-metastatic disease (E0771 tumor cells). Furthermore, PD-1 blockade reduces bone strength compared to
IgG control treatment in mice with bone metastases. These data are consistent with reports of bone loss and
fractures in patients treated with ICIs. I have also found that osteoclast activity and CD8+ T cell populations
capable of secreting pro-osteoclastogenic cytokines are elevated in the bone marrow after PD-1 blockade. I
therefore hypothesize that the detrimental effects of PD-1 blockade on bone stem from CD8+ T cell
expansion, which promotes osteoclast-induced bone destruction, and that tumor resistance to ICIs in
the bone microenvironment stems from T cell dysfunction. I propose to (1) determine how immune cells
influence PD-1 blockade-induced bone loss, and (2) investigate the mechanism behind T cell dysfunction and
tumor resistance to ICIs in the bone microenvironment. In Aim 1 (F99 phase), I will use T cell depletion and
adoptive transfer studies to investigate the role of bone marrow immune cells on PD-1 blockade-induced bone
loss in tumor-inoculated mice. I will also treat tumor-inoculated mice with α-PD-1 in combination with
bisphosphonates to assess prevention of bone loss. In both of these studies, I will assess the bone phenotype
via microCT and biomechanical strength testing, and the tumor and immune phenotypes via flow cytometry and
histology. In Aim 2 (K00 phase), I will utilize digital spatial profiling and scRNAseq technology to characterize T
cell infiltration into bone metastases and identify key signaling pathways between tumor cells, immunoregulatory
cells (myeloid derived suppressor cells, tumor associated macrophages T regulatory cells) and cytotoxic T cells,
which are important in escape of bone metastatic tumor cells from the T cell anti-tumor response. I will use de-
identified human breast cancer samples to validate my findings and elucidate the mechanism(s) by which bone
metastases escape T cell surveillance (e.g., T cell suppression, T cell exhaustion, lack of T cell infiltration into
the tumor microenvironment, etc.). With the current lack of understanding of the mechanism behind bone loss in
patients treated with ICIs and tumor cell resistance to ICIs after bone dissemination, this proposal will help
manage bone health in the millions of patients receiving ICIs each year and confirm mechanistically whether
anti-resorptives reverse ICI-induced bone loss. Furthermore, I...

## Key facts

- **NIH application ID:** 10988974
- **Project number:** 1F99CA294171-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Gwenyth Jean Joseph
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,870
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988974

## Citation

> US National Institutes of Health, RePORTER application 10988974, PD-1 blockade effects on bone strength and metastatic progression (1F99CA294171-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10988974. Licensed CC0.

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