Science: A previously unknown, common mechanism by which cancer cells shut down the anti-cancer immune response

A study by the Ludwig Cancer Research Center found that a single protein was expressed in high amounts in cancer cells with multiple malignancies, establishing a multilayer barrier for the anti-cancer immune response in mouse cancer models, thereby protecting tumors from immune detection and destruction
.

The study, led by Douglas Hanahan of Ludwig Lausanne, two former scientists who worked in his lab, and others, also described a protein-induced gene expression signature called FMRP, which contains 156 different genes and predicts lower
survival rates in patients with multiple types of cancer.
The findings, published in the journal Science, could inform the selection of patients who may benefit from immunotherapy and inform the development of this new treatment for multiple types of cancer
.

Hanahan, a distinguished scholar at the Lausanne branch of the Ludwig Cancer Institute, said: "Our study describes in detail a previously unknown and apparently common mechanism
by which malignant cells shut down the anti-cancer immune response.
" "We have shown that high expression of FMRP, which we and others previously thought was associated with tumor progression, does not directly drive cancer cell proliferation and tumor growth
.
Instead, it supports the ability of malignant cells to
manipulate the type and functional state of surrounding immune cells in a way that is very effective at subverting immune attack.
”

As a protein expressed primarily in neurons, FMRP has been extensively studied as a factor associated with the loss of expression during embryogenesis with the neurodevelopmental disorder Fragile X syndrome, which causes severe intellectual disability
.
Functionally, FMRP is thought to help stabilize the messenger RNA readout of genes in cells and regulate the conversion of this information into proteins
.
But its role in cancer progression is unclear
.

The researchers first showed that FMRP levels were elevated
in many types of tumors.
To test its function in cancer, they used CRISPR-Cas9 gene-editing technology to delete FMR1
, the gene encoding FMRP in mouse cancer cell lines.
They then used these engineered cell lines to create mouse models of pancreas, colon, melanoma and breast tumors and compared them to matching tumors that retained the FMR1 gene, using mice that either had or lacked intact immune systems
.

While all tumors grew similarly in cultured and immunodeficient mice, tumors lacking the FMR1 gene were severely damaged
in mice with normal immune systems.
Helper T cells and cytotoxic T cells also penetrate into cells in large quantities, while helper T cells and cytotoxic T cells play a key role
in anti-cancer immunity.
On the other hand, patients with the intact FMR1 gene progressed rapidly, compared to what they called "immune deserts" — lacking tumor-fighting T cells
.
When T cells were removed from tumors lacking FMR1, they resumed growth, suggesting that FMRP supports tumor progression
through its impact on the immune response.

The researchers found that gene expression programs regulated by FMRP in cancer cells activated multiple defense mechanisms
that support immune evasion.

These include releasing various factors that promote the induction of regulatory T cells (inhibiting the activity of cytotoxic T cells), or reprogramming immune cells called macrophages into a functional state in which they support the growth and survival of cancer cells primarily by pacifying T cells, rather than destroying them
.

At the same time, the loss of FMRP in tumor cells not only reversed its immunosuppressive effects, but also induced them to secrete a factor
that attracts T cells.
In addition, cancer cells lacking FMRP release signals that instruct tumor-infiltrating macrophages to adopt stimulatory procedures that help recruit and activate tumor-killing T cells
.

While FMRP expression itself is not a reliable biomarker of cancer prognosis, the researchers report that gene expression signatures that reflect the regulatory networks it induces consistently predict relatively low odds
of survival for multiple types of cancer.

"We hope that these findings can translate into beneficial diagnoses and treatments for cancer patients, because cancer's signature ability to bypass the immune response underpins resistance to immunotherapy in many types of tumors
," Hanahan said.
At this point, the researchers have isolated a company called Opna Bio, which is developing cancer drugs
that target FMRP and its pathway of action.

Original:

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion