Give immunotherapy cells the elasticity to pass the "stress test"

A previously unknown gene that regulates immunity can revive tired T cells

T cells used for immunotherapy may be depleted in tasks to fight cancer cells or shut down

Ashworth said: "These genomic innovations create avenues

One of the main challenges in developing highly effective cancer immunotherapies is that tumors exist in an environment that inhibits T cells and other immune cells, allowing tumors to form and grow

"By knocking out a single gene, the cells we create are not only effective tumor cell killers, but also more persistent killers over a long period of time," said Julia Carnevale, m.

An unexpected goal

Using a suite of CRISPR screening techniques that allowed them to turn off each gene in the genome one at a time in a group of human T cells, the team identified candidate genes that could make T cells resistant to key aspects of the immunosuppressive microenvironment commonly found in tumors

They are particularly interested in a gene called RASA2 because it has never been linked to immune cell function before

"By focusing on RASA2, we wanted to find out whether controlling the expression of this gene in human T cells might make them more sensitive immunotherapeutic agents

Using a model created by corresponding authors Giedre Krenciute and Justin Eyquem, Ph.

They compared the manifestations of these cells to the original treated T cells, which still contain a functional RASA2 gene

The team tested different types of engineered T cells that block RASA2 and tested cells from many different human donors, as well as liquid and solid cancer models, with consistent

"Knocking out cells allows you to continue killing," Carnevale said

Improve existing treatments

Co-corresponding author Eric Shifrut said: "We want to ensure that when we eliminate the braking effect of RASA2, T cells only recognize and attack cancer cells, not healthy cells

In collaboration with other labs at the institute, researchers are laying the groundwork for clinical trials to improve existing T cell therapies

Carnevale said: "Even in the best case, immunotherapy is not effective for all patients, there are many examples of

Carnevale and Shifrut praised the unbiased and systematic CRISPR screening method for discovering this unknown gene, saying it points the way to unconsidered biology and amplifies the impact of

This study tells us that RASA2 has a previously unexplored role
in immunology.
Similar systematic studies, using CRISPR to look at every gene in the genome, will not only accelerate the design of cancer treatments, but should also contribute to the design of cellular drugs that better treat a variety of diseases, from autoimmune diseases to infectious diseases
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