# Dissecting the Sox2-orchestrated transcriptional network that governs immune resistance in tumor initiating cells

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $407,298

## Abstract

PROJECT SUMMARY
The treatments for various squamous cell carcinomas (SCCs), such as SCCs of the head and neck, have been
revolutionized by the development of immunotherapies. However, even though many treated patients can
evoke robust initial responses, most SCC patients often experience rapid tumor relapse, the nature of which is
still poorly understood. Such hurdles highlight the dire need to uncover novel mechanisms driving
immunotherapy resistance. Understanding tumor relapse after immunotherapy will be vital for advancing
clinical outcomes. Thus, the broad research objective of this proposal is to understand the molecular network
driving tumor relapse from cancer immunotherapy. Cancer immune evasion is a highly complex process
mediated by both an immune suppressive microenvironment and cancer cell-intrinsic resistance mechanisms.
Recently, in a genetically engineered mouse model of SCC, we revealed a group of TGFβ-responding tumor-
initiating cells (TICs) that hijack many molecular features of adult tissue stem cells. Importantly, these cells
appear to be the root of tumor relapse after immunotherapy treatment and are endowed with unique programs
that facilitate their remarkable immune resistance. This key finding raised the importance of identifying the
critical molecular features for these TICs in driving immune resistance in SCCs. In this study, we identified the
pivotal roles of Sox2 as the master transcription factor in orchestrating the TIC-specific immune resistance
program. Here, we will employ an ultrasound-guided in utero lentiviral gene delivery approach to achieve rapid
genetic manipulation of TICs directly in spontaneous SCC tumors. With this powerful technique, we aim to first
identify the Sox2-activated transcriptional network for shaping the immune suppressive microenvironment.
Second, we will dissect the mechanisms of how Sox2 enhances the intrinsic immune resistance of tumor-
initiating cells. Collectively, our proposed study will advance our understanding of the immune resistance
mechanisms specific to TICs and how these mechanisms promote SCC relapse after immunotherapy
treatment. Ultimately, defining the blueprints of the TIC-specific immune evasive mechanisms will open new
avenues to overcome the SCCs recurrence and improve the efficacy of current cancer treatments.

## Key facts

- **NIH application ID:** 10775244
- **Project number:** 1R01CA285786-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Yuxuan Phoenix Miao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $407,298
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10775244

## Citation

> US National Institutes of Health, RePORTER application 10775244, Dissecting the Sox2-orchestrated transcriptional network that governs immune resistance in tumor initiating cells (1R01CA285786-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10775244. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*