Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment

by Selleckchem | Aug 29 2023

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells. Downregulation of IFNAR1 mediated by p38α kinase protected Treg cells from fragility and maintained NRP1 levels, which were decreased in response to IFN1. Genetic or pharmacologic inactivation of p38α and stabilization of IFNAR1 in Treg cells induced fragility and inhibited their immune suppressive and protumorigenic activities. The inhibitor of sumoylation TAK981 (Subasumstat) upregulated IFNAR1, eliciting Treg fragility and inhibiting tumor growth in an IFNAR1-dependent manner. These findings describe a mechanism by which intratumoral Treg cells retain immunosuppressive activities and suggest therapeutic approaches for inducing Treg fragility and increasing the efficacy of immunotherapies.

Comments:

The passage you provided discusses the fragility of regulatory T (Treg) cells and its impact on immune therapies against cancer. Treg cells are a subset of immune cells that play a crucial role in suppressing immune responses to maintain immune balance and prevent excessive inflammation. However, in the context of cancer, Treg cells can hinder the body's immune response against tumor cells, thereby promoting tumor growth.

The fragility of Treg cells refers to their susceptibility to losing their immune suppressive functions and acquiring pro-inflammatory properties, which undermines their ability to control immune responses. In this case, the loss of neuropilin-1 (NRP1) and expression of interferon-gamma (IFNγ) are indicators of Treg cell fragility. These changes make Treg cells less effective in suppressing immune responses and contribute to the success of immune therapies against cancer.

Interestingly, it is observed that Treg cells within the tumor microenvironment somehow avoid fragility. The mechanisms responsible for this protection of intratumoral Treg cells from fragility are not well understood. However, the passage suggests that the downregulation of the IFNAR1 chain, which is part of the type I interferon (IFN1) receptor, plays a role in protecting intratumoral Treg cells.

The downregulation of IFNAR1 on intratumoral Treg cells is mediated by p38α kinase. This downregulation helps protect Treg cells from fragility and maintains the levels of NRP1, which would otherwise decrease in response to IFN1. Inactivation of p38α, either through genetic or pharmacologic means, disrupts this protective mechanism, leading to Treg fragility. When Treg cells become fragile, they lose their immune suppressive and pro-tumorigenic activities.

The passage also mentions an inhibitor of sumoylation called TAK981 (also known as Subasumstat). Sumoylation is a process that regulates protein function by attaching small ubiquitin-like modifiers (SUMOs) to target proteins. The inhibitor TAK981 upregulates IFNAR1 on Treg cells, inducing fragility in these cells and inhibiting tumor growth in an IFNAR1-dependent manner. This suggests that targeting sumoylation could be a potential therapeutic approach to induce Treg fragility and increase the effectiveness of immunotherapies.

Overall, the passage highlights the importance of understanding the mechanisms by which intratumoral Treg cells maintain their immunosuppressive activities. It also suggests potential therapeutic strategies for inducing Treg fragility to enhance the efficacy of cancer immunotherapies.