# Investigating molecular mechanism of immune response during cancer progression

> **NIH NIH K00** · DANA-FARBER CANCER INST · 2024 · $97,605

## Abstract

Project Summary
T cell exhaustion is a dysfunctional T cell state after chronic antigen exposure, and this exhausted T cells
(TEX) are often developed in chronic infection or tumor microenvironment. One of the key features of TEX is
increased expression of inhibitory molecules such as Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and
Programmed Death 1 (PD-1). These molecules work as immune checkpoints to suppress T cell function in
order to prevent pathological damage from T cell hyper-activation. However, in the tumor microenvironment,
these molecules limit the cytotoxic effect of T cells to kill tumor. Blocking these immune checkpoints has
been shown to achieve significant clinical benefits in multiple cancer types. Despite of these successes, the
majority of the patients do not achieve long-term tumor remission. Thus, it is crucial to study the underlying
molecular mechanism of T cell exhaustion development, and seek for potential combination strategies with
immune checkpoint blockade (ICB) to enhance and sustain T cell response in clinic.
During my doctoral research, I focus on investigating the transcriptional mechanisms of T cell exhaustion
development, and how transcription factors control T cell reinvigoration after PD-1 blockade. In Specific Aim
1.1, I focused on the transcriptional mechanisms of effector T cell loss and TEX progenitor establishment
during chronic antigen exposure. Using single cell RNA sequencing (sc-RNA-Seq), we found two distinct
transcriptional networks in the chronic effector T cells and the TEX progenitors, and we systematically
described the molecular mechanism of TEX development. In Specific Aim 1.2, I focus on establishing a T cell
based in vivo CRISPR-Cas9 screening system (RetroCRISPR) to functionally study transcriptional
mechanisms during T cell reinvigoration by PD-1 blockade. These studies will not only discover novel
mechanisms of T cell exhaustion, but also provide high dimensional profiling or high throughput screening
systems for the field to study T cell response. In Specific Aim 2, I plan to extend my RetroCRISPR system
into dissecting the complexity of tumor microenvironment, and I will search for potential combination
strategies with ICB to enhance T cell response. The overall goal for my current projects and future plans is
to discover cell intrinsic and extrinsic mechanisms affecting T cell response, and design optimal immune
therapeutic strategies for long-term tumor remission.

## Key facts

- **NIH application ID:** 10744797
- **Project number:** 5K00CA234842-07
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Zeyu Chen
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $97,605
- **Award type:** 5
- **Project period:** 2018-09-08 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744797

## Citation

> US National Institutes of Health, RePORTER application 10744797, Investigating molecular mechanism of immune response during cancer progression (5K00CA234842-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10744797. Licensed CC0.

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