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Knockdown of T reg Modulator Enhances Antitumor Immunity

A major hallmark of cancer is the ability to “avoid immune destruction, ” and this is aided by regulatory T cells (Tregs). Tregs are an immunosuppressive subset of CD4+ FOXP3+ CD25+ T cells able to hinder immunosurveillance against cancer cells. 
Many studies have shown that Treg infiltration into tumor tissues is associated with poor patient prognosis, and although many attempts to target T regs therapeutically have been studied, there must be a balance between Treg depletion and completely suppressing autoimmunity. Additionally, studies performed in cancer mouse models suggest that inducing a more “fragile” Treg phenotype leads to better response to PD-1 blockade.
Given that modulation of Tregs is a possible therapeutic strategy, Cortez et al. investigated what nuclear factors regulate Tregs using a CRISPR based pooled screen for Foxp3 expression in primary mouse T reg cells. Of the 489  factors screened, several unknown modulators of Foxp3 were identified to modulate Foxp3 expression. The authors were particularly interested in USP22 and followed up with further studies on its role as a Treg modulator.

The ubiquitin-specific peptidase 22 (Usp22) is a deubiquitylase able to remove ubiquitin from various substrates and thereby regulate protein activity. Overexpression of Usp22 has been previously associated with both poor cancer prognosis. Usp22 was validated as a positive regulator for Foxp3 in human Treg cells and further studied using a mouse model for Treg specific ablation of Usp22. The model also showed decreased levels of Foxp3 in Usp22 knockout Tregs, as well as reduced Treg number and reduced Treg function measured by the suppression of T effector cells.

Given that Usp22 is part of the chromatin-modifying SAGFA complex, the authors next wanted to determine if their hypothesis was correct that Usp22 Foxp3 modulation was occurring at the transcriptional level. They discovered that Usp22 can modulate Foxp3 both at the transcript level and at the protein level with loss of Usp22 resulting in increased ubiquitin dependent degradation of Foxp3.

The authors then wanted to evaluate the effect of Treg specific knockdown in disease. Lymphoma tumor growth was inhibited by Usp22 Treg gene deletion, and upon examination of immune cells, effector T cells along with other cytotoxic lymphocytes were increased while Treg tumor infiltration and numbers were decreased.
  
Overall this work suggests that Usp22 ablation leads to more fragile and less suppressive Tregs allowing for a better antitumor immune response. In recent years, antibodies have been studied as the main mechanism to induce Treg fragility. A few groups have shown antibody-mediated suppression of Tregs can induce an antitumor immune response and that Treg suppression exhibits synergy with PD-1 blockade. Based on the data presented in this paper, inhibition of Treg transcriptional modulators like USP22 could also be a viable approach.

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