# Regulation of CD8+T cells by Zbtb42

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $408,469

## Abstract

ABSTRACT:
Effector CD8+T cells that promote anti-tumor response become dysfunctional and exhausted. However, the key
mechanisms that define the delicate balance between effector vs. exhausted state of CD8+T cells remain elusive.
Our preliminary studies demonstrate that in early-stage tumors, sumoylation of the T-box transcription factor, T-
bet, facilitates its association with Zbtb42, a member of the ThPOK family of transcription factors. The Zbtb42/T-
bet complex promotes the effector function and anti-tumor activity of CD8+ tumor-infiltrating lymphocytes (TILs).
Conversely, in advanced tumors, the ubiquitin ligase Trim37 is upregulated in exhausted CD8+TILs, which
targets Zbtb42 for degradation and disrupts the Zbtb42/T-bet complex. Importantly, CRISPR-Cas9-mediated
inhibition of Trim37 rescues exhausted CD8+TILs and restores their effector function. These key findings led us
to hypothesize that ubiquitination and sumoylation of the Zbtb42/T-bet complex are critical molecular events that
dictate the effector vs. exhaustion of CD8+TILs, which can be therapeutically targeted.
In Aim1, we will determine the mechanism by which the Zbtb42/T-bet complex promotes effector CD8+T cell
function and anti-tumor response. We will use newly generated Zbtb42-/- and T-bet-K208R-KI mice to investigate
how sumoylation of T-bet at Lys(K)-208 facilitates the formation of the Zbtb42/T-bet complex via the SUMO
interacting motif (SIM) within Zbtb42. Further, we will delineate the mechanism by which the Zbtb42/T-bet
complex co-operatively binds to and transactivates the IFN-γ promoter. In Aim 2, we will investigate how Trim37,
which is upregulated in exhausted (PD1+Tim3+) CD8+TILs in advanced tumors, binds to Zbtb42 via its meprin
and TRAF homology (MATH) domain and targets Zbtb42 for ubiquitination at K164. Using newly generated
Trim37-/- mice, we will examine how disruption of the Zbtb42/T-bet complex leads to the inhibitory transcriptional
profile of exhausted CD8+T cells in advanced tumors. In Aim 3, we will target the Zbtb42-Trim37 pathway in
CAR-T cells to promote tumor regression. We will test the therapeutic potential of blocking Zbtb42 ubiquitination
in CAR-T cells against carcinoembryonic antigen (CEA) in the MC38 and a patient-derived xenograft (PDX)
colon cancer model.
Completion of these studies will lead to 1) discovery of the novel Zbtb42/T-bet complex that is critical for effector
CD8+T cell function, 2) determination of how Trim37-mediated ubiquitination disrupts this complex leading to
alternate transcription profile in exhausted CD8+TILs, and 3) evaluate the means to target the Zbtb42/T-bet-
Trim37 pathway to overcome the current limitations of CAR-T cell therapy for solid tumors.

## Key facts

- **NIH application ID:** 10915049
- **Project number:** 5R01CA266072-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Venuprasad K Poojary
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,469
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915049

## Citation

> US National Institutes of Health, RePORTER application 10915049, Regulation of CD8+T cells by Zbtb42 (5R01CA266072-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10915049. Licensed CC0.

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