# Characterizing the regulation of PD-1 ligands in head and neck cancer stem cells using an autologous humanized model with T cell education capability

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $467,285

## Abstract

SUMMARY
An obstacle to studying human cancer is the limited availability of models with human stroma and immune
cells. This is particularly relevant for head and neck squamous cell carcinomas (HNSCC) given the pivotal role
the immune system plays in their development. An unmet need is an investigation of how cancer stem cells
(CSCs) modulate immunity, because it is critical to understand how CSCs harness oncogenic signaling to
evade immune surveillance. To address these outstanding questions, we will use two unique tools: 1) CSCs
derived from a panel of patient HNSCCs propagated in mice, and 2) a humanized mouse (HM) model that
enables studying tumor-stromal interactions. We have defined CSCs as ALDH+CD44high in multiple patient
cases, and documented that SOX2 is responsible for key CSC features such as growth, invasion, and
resistance to therapy (1). Further, we observed an association between SOX2 and tumor expression of the
ligand PD-L1, which activates PD-1 in T cells leading to immune escape. Additionally, SOX2 modulates SOX9,
which regulates the other PD-1 ligand, PD-L2. After treatment of HNSCC HM mice with a PD-1 inhibitor, we
documented resistance associated with an increase in PD-L2; thus, we propose that alternate ligands are used
by HNSCC as a resistance mechanism. We initially developed a mismatched HM (mHM; tumor and
hematopoietic stem cells [HSCs] from different sources), and now have generated an autologous HM (aHM;
tumor, HSCs and mesenchymal stem cells [MSCs] from the same patient). Tumors grown in HM more closely
resemble the originator tumor than those grown in non-HM mice, and the drift in gene expression caused by
prior passaging was partially reversed. Signaling in key immune and stroma pathways was more prominent
and closely resembled the originator patient in HM vs. non-HM models. The immune cells mounted effective
tumor-specific immune responses, mediated by human immune cells including T cells. Two salient and under-
studied issues limit the wider application of HM: tumor-immune mismatch and T cell education. Tumor and
immune matching can affect the faithfulness of immune response, and that can only be appreciated by
comparing mHM and aHM. HM are subject to xenogeneic education of human T cells by mouse thymic cells,
resulting from the lack of a functional human thymus in such models. The goals of this proposal are to: 1) study
the regulation by SOX2 and SOX9 of PD-1 ligands; 2) understand how SOX2 and SOX9 affect CSC
properties; 3) generate and characterize aHM and mHM from 10 HNSCC patients; 4) test if SOX2 and SOX9
are involved in resistance to PD-1 inhibitors by testing them on HM; and finally, we will 5) generate thymic
epithelium from the same patient's HSCs that will result in HM with a fully autologous HNSCC, thymus and
immune system, thus enabling immune cell education in a strictly human context. This project will lead to a
deeper and more mechanistic understanding of the interplay between HNSCC CSCs and the i...

## Key facts

- **NIH application ID:** 10174772
- **Project number:** 5R01CA149456-10
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Antonio Jimeno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,285
- **Award type:** 5
- **Project period:** 2010-08-09 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174772

## Citation

> US National Institutes of Health, RePORTER application 10174772, Characterizing the regulation of PD-1 ligands in head and neck cancer stem cells using an autologous humanized model with T cell education capability (5R01CA149456-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10174772. Licensed CC0.

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