# Dissecting Stem Cell Intrinsic Signaling Driving Tumor Relapse from Immunotherapy

> **NIH NIH R00** · UNIVERSITY OF CHICAGO · 2020 · $249,000

## Abstract

PROJECT SUMMARY
Tumors are initiated and maintained by a stem cell-like population. However, our bodies have a powerful
immune surveillance system to clear out cancerous cells as they emerge. Whether tumor-initiating stem cells
(tSCs) are programmed to resist anti-tumor immunity and/or how they overcome the barrier of immune
surveillance remains poorly understood. Previously, we have designed a novel skin squamous cell carcinoma
(SCC) mouse model that can be effectively targeted by adoptive T cell transfer (ACT) based immunotherapy,
in which the CD8+ cytotoxic T cells are engineered to recognize a tumor-specific neoantigen, then are
activated and reintroduced to the body to attack tumor. In this model, we have successfully demonstrated that
a subset of tSCs are surprisingly refractory to the antigen-specific T cell treatment, and cause the tumor to
relapse. Since tumor relapse is a major clinical obstacle for patients receiving ACT, understanding the factors
that sustain immune evasive SCs is paramount for limiting relapse in ACT. Therefore, with my strong
background in immunology, I'm especially interested in how these highly plastic stem cells receive special cues
to develop resistance or become evasive to the anti-tumor immunity. Our preliminary data shows that tSCs
must sequentially undergo three stages involving distinct immune evasive. Specifically, the tSCs must firstly,
endure massive T cell attack during the initial primary tumor clearance stage; then become quiescent while still
evade immune detection to maintain a long period of dormancy; finally, exclude the infiltrating T cells in order
to exit dormancy and generate relapsed tumors. We hypothesize that specific signaling cue activates different
cohort of genes in stem cells during each of the three stage of tumor relapse and dictates stage-specific
immune evasive program. Driven by this hypothesis and built on strong preliminary data, I found that Wnt/β-
Catenin signaling, an essential pathway for stem cell functions is critical in each of these three stages of tumor
relapse. Now I designed comprehensive research aims to systematically interrogate the stem cells and sought
to identify Wnt-regulated genes and their mechanisms promoting each stage of tumor relapse from ACT
treatment. My plan for the remainder of my postdoctoral training is to acquire additional skills and develop
research tools to tackle this fascinating question, and to open a door for establishing independence in
academia. My long-term research objective is to identify new druggable targets that could potentially lead to
next generation of immunotherapy that is designed to eliminate the tSCs. I expect the originality of my
approaches and identification of novel Wnt targets regulating tumor immune evasion will allow me to build a
solid foundation for a future independent research program. More importantly, I expect that the data generated
from my related but independent aims will unveil new tumor-intrinsic targets tha...

## Key facts

- **NIH application ID:** 10200232
- **Project number:** 4R00CA237859-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Yuxuan Phoenix Miao
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200232

## Citation

> US National Institutes of Health, RePORTER application 10200232, Dissecting Stem Cell Intrinsic Signaling Driving Tumor Relapse from Immunotherapy (4R00CA237859-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200232. Licensed CC0.

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