Study reveals mechanism by which malignant cells turn off immune responses against cancer

Study reveals mechanism by which malignant cells turn off immune responses against cancer

A study from Ludwig Cancer Research has uncovered a single protein expressed at high levels by cancer cells in a broad range of malignancies that creates a multilayered barrier to anti-cancer immune responses in mouse models of cancer, protecting tumors from detection and destruction by the immune system.

Led by Douglas Hanahan of Ludwig Lausanne, two former scientists in his lab, Qiqun Zeng and Sadegh Saghafinia, and graduate student Agnieszka Chryplewicz, the study also describes a signature of gene expression induced by the protein called FMRP, which includes 156 different genes and poorly predicts patient survival in several types of cancer. The findings, reported in the journal Science, if developed further, could influence the selection of patients likely to benefit from immunotherapies and the development of new such therapies for multiple cancer types.

Our study has detailed a previously unknown and apparently common mechanism by which malignant cells turn off the immune response against cancer. We have shown that the hyperexpression of FMRP, which we and others have previously linked to tumor progression, does not directly drive cancer cell proliferation and tumor growth. Rather, it supports the ability of malignant cells to manipulate the types and functional states of immune cells around them in a way that is very effective at subverting an immune attack.

Douglas Hanahan, Distinguished Scholar at the Ludwig Institute for Cancer Research Lausanne Branch

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

The researchers first showed that FMRP levels are elevated in several tumor types. To study its function in cancer, they applied CRISPR-Cas9 gene editing to delete FMR1, the gene encoding FMRP, in mouse cancer cell lines. They then used the engineered cell lines to create mouse models of pancreatic, colon, melanoma and breast tumors and compared them to matched tumors that retained their FMR1 genes, using mice that either had an intact immune system or not.

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While all tumors grew similarly in culture and in immunocompromised mice, those lacking the FMR1 gene were severely impaired in mice with competent immune systems. They were also heavily infiltrated with helper and cytotoxic T cells, which play a central role in cancer immunity. Those with intact FMR1 genes, on the other hand, developed aggressively and were, in comparison, so-called “immune deserts” – without anti-tumor T cells. When T cells were removed from the FMR1-deficient tumors, they resumed growth, suggesting that FMRP supports tumor progression through its effects on the immune response.

The researchers discovered that the gene expression program regulated by FMRP in cancer cells activates multiple defense mechanisms that support immune evasion.

This involves releasing factors that variously promote the induction of regulatory T cells – which suppress the activity of cytotoxic T cells – or reprogram immune cells known as macrophages into a functional state in which they support the growth and survival of cancer cells rather than their destruction, primarily by pacifying T cells.

Loss of FMRP in cancer cells, on the other hand, not only reversed their immunosuppressive effects but also induced the secretion of a factor that attracts T cells. In addition, the FMRP-deficient cancer cells released signals that instructed tumor-infiltrating macrophages to adopt a stimulatory program that helped recruit and activate tumor-killing T cells.

While FMRP expression itself is not a reliable prognostic biomarker of cancer outcomes, the researchers report that a signature of gene expression that reflects the regulatory network that induces it consistently predicts relatively poor survival outcomes across multiple cancer types.

“We hope that these discoveries can be translated into diagnostics and therapies to benefit cancer patients, as the distinctive ability of cancers to evade immune responses underlies the resistance of many tumor types to immunotherapy,” Hanahan said. To this point, researchers have spun off a company called Opna Bio that is developing cancer drugs that target FMRP and the pathways through which it exerts its effects.

Source:

Ludwig cancer research

Reference:

Saghafinia, S., et al. (2022) Aberrant hyperexpression of the RNA-binding protein FMRP in tumors mediates immune evasion. Science. doi.org/10.1126/science.abl7207.

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