# Investigating TOX2 as a novel regulator of T cell memory differentiation

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $45,520

## Abstract

PROJECT ABSTRACT
Recent scientific advancements have made immunotherapy a promising option for many cancer patients.
Immunotherapy can bolster the ability of the immune system to recognize and destroy cancer cells. However,
not all patients respond to immunotherapy, thus a better understanding of the mechanisms that underlie
immune cell effector function is required to improve response rates. In collaboration with Dr. Carl June's group,
our lab recently studied a CLL patient who had gone into complete remission following CAR-T therapy. We
found that an overwhelming majority of the CAR+ cells had a disruption in the TET2 gene, and experimental
knockdown of TET2 resulted in enhanced proliferative capacity and anti-tumor activity of CAR T cells in vitro.
Furthermore, T cells with the TET2 knockdown displayed increased expression of TOX2, a member of the
HMG-box family of DNA-binding proteins. TOX2 is an immune-specific transcription factor expressed in the
human spleen and tonsils. Interestingly, the only known function of TOX2 is that it positively regulates the
transcription factor T-BET during the development of natural killer cells, by repressing the inhibitory PD-1
protein. Owing to the increase in TOX2 mRNA levels in TET2 knockdown CAR T cells, in addition to its ability
to downregulate a key inhibitory receptor, I hypothesize that TOX2 is a positive regulator of T cell effector
function due to its ability to upregulate T-BET. To test this hypothesis, I will pursue three aims. Aim 1 is to
manipulate TOX2 expression in human T cells to determine whether it improves T cell differentiation and
effector function. Aim 2 is to determine the pattern of TOX2 binding to the genome, with the goal of identifying
its transcriptional targets, at both the mRNA and protein levels. Very little is known about how HMG-box
proteins bind chromatin in vivo. Thus, this aim will also provide a more fundamental understanding of the
chromatin functions of HMG proteins. Aim 3 is to determine levels of TOX2 mRNA in CLL patients who have
received CAR T therapy, to determine whether higher TOX2 levels are predictive of better response to CAR T
therapy. This study could elevate TOX2 as a novel target for improving CAR T cell function. An understanding
of the molecular mechanisms could make it possible to activate TOX2, ultimately improving patient responses
to immunotherapy.

## Key facts

- **NIH application ID:** 9932793
- **Project number:** 5F31CA239428-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sierra McDonald
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932793

## Citation

> US National Institutes of Health, RePORTER application 9932793, Investigating TOX2 as a novel regulator of T cell memory differentiation (5F31CA239428-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932793. Licensed CC0.

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