# The deubiquitinase USP17LA negatively regulates T-cell activation and attenuates anti-tumor immunity

## TL;DR

This study identifies USP17LA as a negative regulator of T-cell activation and shows that its loss enhances anti-tumor immunity in mice.

## Contribution

The study reveals USP17LA as a novel negative regulator of T-cell activation and a potential target for cancer immunotherapy.

## Key findings

- USP17LA-deficient T cells show increased cytokine production and anti-tumor activity in murine models.
- USP17LA interacts with RACK1 to suppress NFAT signaling, inhibiting T-cell function.
- Deleting Usp17la improves TCR signaling and tumor surveillance without affecting T-cell development.

## Abstract

T-cell activation is essential for effective immune responses, yet its precise regulatory mechanisms remain incompletely understood. In this study, we show that the deubiquitinases of the Ubiquitin-Specific Peptidase 17-like (USP17L) family are significantly upregulated following T-cell stimulation. Using CRISPR-mediated gene knockout mice, we demonstrate that USP17LA, but not USP17LB, acts as a negative regulator of T-cell activation. Loss of Usp17la leads to increased production of pro-inflammatory cytokines, enhanced T-cell proliferation and effector functions, without affecting T-cell development or homeostasis. Furthermore, Usp17la deletion augments TCR signaling and anti-tumor immunity, improving T-cell-mediated tumor surveillance in murine tumor models. Mechanistically, proteomic analysis revealed that USP17LA strongly associates with cadherin-binding and calmodulin-binding pathways. Notably, USP17LA interacts with RACK1 and prevents its ubiquitin-dependent degradation, thereby promoting RACK1-mediated suppression of NFAT activity and the subsequent inhibition of T-cell function. These findings establish USP17LA as a pivotal modulator of T-cell activation and suggest that targeting USP17LA could enhance anti-tumor immunity, offering a potential strategy for cancer immunotherapy.

USP17LA loss enhances T-cell function and anti-tumor activity in murine tumor models.

Usp17la-deficient T cells exhibit enhanced cytokine production, proliferative capacity, and anti-tumor activity.USP17LA deubiquitinates RACK1 to negatively regulate NFAT signaling.USP17LA represents a potential therapeutic target in cancer immunotherapy.

Usp17la-deficient T cells exhibit enhanced cytokine production, proliferative capacity, and anti-tumor activity.

USP17LA deubiquitinates RACK1 to negatively regulate NFAT signaling.

USP17LA represents a potential therapeutic target in cancer immunotherapy.

USP17LA loss enhances T-cell function and anti-tumor activity in murine tumor models.