# Znf740 in the regulation of CD8+T cell exhaustion

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $534,291

## Abstract

ABSTRACT:
CAR-T cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid
tumors, because the effector CD8+T cells become dysfunctional and exhausted in the tumor microenvironment
(TME). However, the key pathways that define the delicate balance between the effector vs. exhausted state of
CD8+T cells remain unclear. Our preliminary data demonstrate that Znf740, a novel member of the zinc finger
family of transcription factors, is critically essential for effector CD8+T cells. Znf740 binds to SUMOylated T-bet
and promotes the effector function and anti-tumor activity of CD8+ tumor-infiltrating lymphocytes (TILs).
Conversely, in exhausted PD1+Tim3+CD8+T cells, Znf740 expression is downregulated, which disrupts the
Znf740:T-bet complex. Importantly, reconstitution of Znf740 expression rescues exhausted CD8+TILs and
restores their effector function. Further, transgenic expression of Znf740 in CD8+T cells resulted in reduced tumor
growth which was associated with elevated IFN- production by TILs. These key findings led us to hypothesize
that the Znf740:T-bet complex is critically essential for the effector function of CD8+T cells, and the disruption of
this complex in PD1+Tim3+ cells promotes exhaustion of CD8+TILs which can be therapeutically targeted.
In Aim1, we will investigate how Znf740 promotes effector CD8+T cell function and anti-tumor response. Using
newly generated Znf740-/- and T-bet-K208R knock-in mice, we will delineate the mechanism by which Znf740
binds to T-bet through its SUMO-interacting motif (SIM) to form the Znf740:T-bet complex and transactivates the
IFN- promoter in effector CD8+TILs. In Aim 2, we will target Znf740 to overcome T cell exhaustion and promote
tumor regression. We will investigate how disruption of the Znf740:T-bet complex in advanced tumors promotes
an alternate transcription profile of PD1+Tim3+ exhausted TILs. Using newly generated T cell-specific Znf740
transgenic mice, we will test the effect of overexpressing Znf740 in CAR-T cells against carcinoembryonic
antigen (CEA) in the MC38 colon cancer model. Finally, the therapeutic potential of overexpressing Znf740 in
CAR-T cells will be tested in colon cancer patient-derived xenograft (PDX) models.
Completion of these studies will result in the establishment of 1) a novel Znf740:T-bet complex that is critical for
the effector CD8+ T cell function, 2) determine how reduced Znf740 expression disrupts this complex leading to
alternate transcription profile in exhausted CD8+ TILs in advanced tumors, and 3) evaluate the means to target
the Znf740 to overcome the current limitations of CAR-T cell therapy for solid tumors. This could lead to clinical
trials using "Exhaustion Resistant CAR-T cells" for improved outcomes in patients with advanced tumors.

## Key facts

- **NIH application ID:** 10906872
- **Project number:** 5R01CA282143-02
- **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:** $534,291
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906872

## Citation

> US National Institutes of Health, RePORTER application 10906872, Znf740 in the regulation of CD8+T cell exhaustion (5R01CA282143-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10906872. Licensed CC0.

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