A deubiquitination module essential for T _reg fitness in the tumor microenvironment

Abstract

The tumor microenvironment (TME) enhances regulatory T (T reg ) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T reg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T reg fitness. We demonstrate that TME-specific stressors including transforming growth factor–β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 ( Usp22 ) and Usp21 , by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T reg fitness. Simultaneous deletion of both USPs in T reg cells largely diminishes TME-induced Foxp3 up-regulation, alters T reg metabolic signatures, impairs T reg -suppressive function, and alleviates T reg suppression on cytotoxic CD8 + T cells. Furthermore, we developed the first Usp22 -specific small-molecule inhibitor, which dramatically reduced intratumoral T reg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying T reg fitness and identify Usp22 as an antitumor therapeutic target that inhibits T reg adaptability in the TME.

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis

“…In fact, pharmacological USP22 inhibition dramatically reduced the frequency of breast cancer stem cells and attenuated both mouse and human invasive breast cancer lung metastasis. In addition to its cancer cell-intrinsic roles, USP22 has been recently discovered to suppress tumor immunosurveillance through potentiating Foxp3 + regulatory functions 31,41 as well as upregulating the expression of checkpoint receptors PD-L1 and CD73 42,43 . Therefore, USP22 targeting presumably achieves both chemo-and immune-therapeutic e cacy.…”

“…We rst analyzed the effects of pharmacological USP22 inhibition on BCSCs self-renewal using a small molecule inhibitor USP22i-S02 that we recently identi ed (Fig. 5A) 31 . Similar to our observation from USP22 CRISPR KO studies, treatment of breast cancer cells 4T1 and TN1 signi cantly inhibited both integrin b1 and FoxM1 expression.…”

USP22 overexpression fails to augment tumor formation in MMTV-ERBB2 mice but loss of function impacts MMTV promoter activity

“…Increased frequencies of regulator T cells (T-regs) occur in the microenvironment of a variety of malignancies, including breast cancer, and increased numbers of circulating T-regs have been suggested to contribute to the higher metastatic potential of Her-2/neu-positive cells [31]. Others have shown a role for Usp22 in regulating anti-tumor immunity through the modulation of T-regs [32, 33] and future studies using deletion or overexpression of Usp22 in Tregs within a mouse breast cancer model could lead to significant insights to how Usp22 overexpression affects tumorigenesis. In addition, given our previous findings that Usp22 loss impacts placental vascularization [16], it would also be interesting to determine whether overexpression of USP22 in endothelial cells affects tumor progression through enhanced angiogenesis [34].…”

Targets of tumor microenvironment for potential drug development

“…This inhibitor significantly decreased Foxp3 expression in intratumoral Treg cells, further amplifying antitumor immunity. 46 These studies provided valuable insights into the mechanisms by which Treg cells modulate immune responses in the TME and paves new paths for therapeutic interventions targeting intratumoral Treg cells to boost antitumor immunity.…”