A Novel Engineered Protein Boosts T Cell Antitumor Activity

Immunotherapies such as immune checkpoint inhibitors and CAR T cell therapy, which boost the cancer-fighting properties of patients’ own immune cells, have revolutionized the treatment of cancer. However, prolonged exposure to tumor antigens can still result in T cell exhaustion, characterized by reduced function and self-renewal.¹ This hinders their sustained attack and reduces the effectiveness of immunotherapies that employ these cells. As such, scientists have been researching ways to “un-exhaust” tumor-associated T cells.

Now, researchers have engineered a protein that reduced the expression of exhaustion-related genes and enhanced T cell survival within tumors.² Their results, published in Science Immunology, highlight an approach to rewire cytotoxic T cell (CTL) signaling and boost antitumor immunity.

Continue reading below...

Cancer

A Rare White Blood Cell Boosts Cancer-Fighting Immune Cells

Read More

The research team, led by Adam Courtney, an immunologist at the University of Michigan, drew inspiration from the Herpesvirus saimiri virus (HVS) that infects primates and hijacks the signaling in their lymphocytes to reproduce. HVSs express the tyrosine kinase interacting protein (TIP), which recruits a T cell-enzyme called lymphocyte-specific protein tyrosine kinase (LCK), triggering a signaling cascade leading to T cell replication and eventual transformation to cancerous cells.³

Courtney and his team sought to exploit this property of TIP to stimulate T cells without interfering with their function. They obtained TIP variants that contained the regions responsible for binding to LCK but not for affecting T cell activity. Treating cultured T cells with the engineered proteins did not have a detrimental effect on T cell function, but induced LCK enzyme activity.

From the collection of engineered proteins, the researchers identified one that could recruit LCK to activate signal transducer and activator of transcription 5 (STAT5), which plays a critical role in T cell homeostasis and expansion.⁴ They dubbed this protein aSTAT5. To examine whether aSTAT5 maintained the cytotoxic capacity of CTLs, the researchers cultured aSTAT5-treated T cells with colon cancer cells. Increased cancer cell death indicated that aSTAT5 could maintain CTL function. Importantly, STAT5-activating pro-survival cytokines are depleted by the tumor microenvironment, suggesting that aSTAT5 could be used to boost anticancer properties of T cells.⁵

Courtney and his team then validated the results in vivo by isolating T cells from tumor-bearing mice, treating the cells with aSTAT5, and injecting the cells back into the mice. They monitored the tumors and found that compared to untreated T cells, adoptive transfer of aSTAT5-treated T cells delayed tumor growth. Comparing the T cell populations in mice that received control or aSTAT-5 treated T cells revealed that the latter had increased persistence, activation, and cytokine production.

Continue reading below...

Cancer

Meet Cyclone: A Monitoring Tool That Watches for Waves of Immune Response

Read More

Finally, the researchers investigated the mechanism by which aSTAT5 promoted CTL survival and function in the tumor. Single-cell RNA sequencing of tumor-infiltrating CTLs in mice that received adoptive T cell therapy with aSTAT5-treated cells showed reduced expression of genes associated with an exhausted T cell fate. Moreover, aSTAT5 sustained the expression of pro-survival genes in these cells.

According to the researchers, their results indicate that STAT5 is an important mediator of T cell exhaustion in tumors. They hypothesized that combining STAT5 activation with treatments like CAR T therapy could be an effective immunotherapeutic strategy. However, the researchers cautioned that the efficacy and safety of such an approach in humans remains to be determined.