Engineered Viral Protein Enhances T Cell Antitumor Activity by Reversing Exhaustion.

In a significant advancement in cancer immunotherapy, scientists at the University of Michigan have engineered a protein that revitalizes exhausted T cells, bolstering their ability to combat tumors. The study, led by immunologist Adam Courtney and published in Science Immunology, introduces a protein named aSTAT5, designed to sustain T cell activity within the tumor microenvironment.

T cell exhaustion, a state where T cells lose their efficacy due to prolonged exposure to tumor antigens, poses a major challenge to therapies like CAR T cell treatment and immune checkpoint inhibitors. To address this, Courtney's team drew inspiration from the Herpesvirus saimiri (HVS), which infects primates and manipulates their immune cells to replicate. HVS produces a protein called tyrosine kinase interacting protein (TIP) that recruits the enzyme lymphocyte-specific protein tyrosine kinase (LCK), initiating a cascade that leads to T cell proliferation.

The researchers engineered variants of TIP that retained the ability to bind LCK without disrupting T cell function. Among these, they identified a variant capable of activating signal transducer and activator of transcription 5 (STAT5), a protein crucial for T cell survival and proliferation. This engineered protein, dubbed aSTAT5, was tested on cultured T cells exposed to colon cancer cells. The treated T cells demonstrated enhanced cancer cell killing, indicating that aSTAT5 preserved their cytotoxic function.

Further validation involved isolating T cells from tumor-bearing mice, treating them with aSTAT5, and reintroducing them into the mice. The aSTAT5-treated T cells exhibited increased persistence, activation, and cytokine production, leading to delayed tumor growth compared to controls. Single-cell RNA sequencing revealed that these T cells had reduced expression of genes associated with exhaustion and maintained pro-survival gene expression.

The findings suggest that STAT5 plays a pivotal role in T cell exhaustion within tumors. By activating STAT5 through aSTAT5, T cells can be reprogrammed to resist exhaustion, enhancing their antitumor capabilities. This approach holds promise for improving the efficacy of existing immunotherapies, including CAR T cell therapy. However, the researchers caution that further studies are necessary to assess the safety and effectiveness of aSTAT5 in human applications.

This innovative strategy represents a potential leap forward in cancer treatment, offering a method to rejuvenate the body's own immune response against tumors.

Source:https://www.the-scientist.com/a-novel-engineered-protein-boosts-t-cell-antitumor-activity-73035

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