# Reprogram long-lived effector T cells for cancer immunotherapy

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $594,393

## Abstract

Program Description/Abstract
Adoptive cell therapy (ACT), including the use of T cells engineered to express chimeric antigen receptors
(CARs), has produced unprecedented clinical outcomes and represents a new paradigm in cancer
immunotherapy. However, the therapeutic efficacy is often limited by poor in vivo persistence and function of
adoptively transferred T cells. How T cell fate decisions between robust effector function and long-term
persistence are regulated in the tumor microenvironment (TME) remains poorly understood. Moreover, T cells
undergo extensive metabolic reprograming during their activation and differentiation, but how metabolic fitness
is linked to T cell function and longevity is unclear. In our preliminary studies, through an in vivo pooled CRISPR-
Cas9 mutagenesis screening of metabolism-associated factors, we identified the enzyme Regnase-1 (Reg1) as
a major negative regulator of antitumor CD8 T cell responses. Deletion of Reg1 resulted in drastically improved
intratumoral CD8 T cell accumulation and therapeutic efficacies against mouse solid and blood cancers. Reg1-
null CD8 T cells were reprogrammed in TME to acquire better persistence, survival advantage and naïve/memory
cell-associated gene signatures, but also retain potent effector function and enhanced mitochondrial metabolism.
To explore the underlying mechanisms and additional targets, we performed a secondary in vivo genome-scale
CRISPR-Cas9 screening in Reg1-null CD8 T cells and uncovered BATF as the key functional target of Reg1 in
shaping mitochondrial metabolism and effector function of CD8 T cells. We also identified additional factors as
putative targets for combinatorial therapy, as their co-deletion further potentiated the antitumor activity of
Regnase-1-null cells. Our central hypothesis is that tumor-specific CD8 T cells can be reprogrammed to be
long-lived effector T cells with adaptive metabolic and transcriptional programs, and targeting Regnase-
1 and associated pathways is an innovative strategy for cancer immunotherapy. Aim 1. Establish Reg1-
BATF-dependent mitochondrial metabolism in tumor-specific CD8 T cells. Aim 2. Dissect mechanistic basis
underpinning the stemness features of tumor-specific CD8 T cells. Aim 3. Explore the therapeutic potential of
targeting Reg1 and combinatorial factors. We predict our studies will establish a new paradigm in understanding
fundamental mechanisms of T cell fate decisions and immunometabolism and provide new avenues to improve
ACT efficacy in cancer immunotherapy.

## Key facts

- **NIH application ID:** 9998403
- **Project number:** 1R01CA250533-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Hongbo Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $594,393
- **Award type:** 1
- **Project period:** 2020-03-06 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998403

## Citation

> US National Institutes of Health, RePORTER application 9998403, Reprogram long-lived effector T cells for cancer immunotherapy (1R01CA250533-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998403. Licensed CC0.

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