# Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis

> **NIH NIH U54** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $633,251

## Abstract

PROJECT SUMMARY
Project I. Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis
CD8 T cells are powerful components of the immune system that have the potential to selectively eradicate
cancer cells, however, in most patients, tumors progress relentlessly despite the presence of tumor-specific
CD8 T cells. We developed a genetic cancer mouse model that faithfully mirrors cancer development in
patients and revealed that tumor-specific CD8 T cells enter a state of dysfunction early during tumorigenesis.
These T cells exhibited the hallmarks of dysfunctional T cells from late-stage human tumors. Early after tumor
initiation, T cell dysfunction was plastic, but at later times, became fixed. Breakthrough therapies (immune
checkpoint blockade) have emerged to reverse T cell dysfunction but these strategies have only worked in a
subset of patients and a subset of tumor types. The goal of Project I is to understand the co-evolutionary
cancer cell, stromal and immune population dynamics that control T cell differentiation to different functional
states and consequently, T cell sensitivity to immunotherapeutic interventions. We will leverage the power of
clinically-relevant genetic cancer mouse models to dissect the complex interplay of cancer genomic evolution,
immune and stromal cell population dynamics, and the molecular mechanisms controlling CD8 T cell
differentiation using innovative single-cell transcriptional and epigenetic analytic tools and powerful
mathematical modeling approaches. In Aim 1, we will define the chromatin states and/or transcription factor
networks that mediate the transition between functional, plastic dysfunctional, and fixed dysfunctional T cell
states. In Aim 2, we will characterize the mutational tumor antigen landscape, stromal and immune cell
population dynamics, and TCR repertoire, and build and test a mathematical model to predict how these tumor
parameters determine T cell functional states. In Aim 3 we will determine whether tumor-specific T cells in
human solid tumors exist in heterogeneous functional states that predict responsiveness to immune checkpoint
blockade therapy. By bringing together considerable expertise in cancer immune mouse modeling,
computational methods, and clinical immune checkpoint blockade therapy, these approaches will provide new
insights into T cell differentiation and could novel strategies to unleash the precise power of tumor-specific CD8
T cells for cancer immunotherapy.

## Key facts

- **NIH application ID:** 9980808
- **Project number:** 5U54CA209975-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Andrea Schietinger
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $633,251
- **Award type:** 5
- **Project period:** 2016-08-26 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980808

## Citation

> US National Institutes of Health, RePORTER application 9980808, Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis (5U54CA209975-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9980808. Licensed CC0.

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