Common mechanism tumours use to suppress immune responses: Study

BRUSSELS: A single protein expressed at high levels by cancer cells across a wide range of malignancies has been identified by Ludwig Cancer Research researchers. This protein constructs a complex barrier to anti-cancer immune responses in mouse models of cancer, protecting tumours from immune detection and destruction.

The study, led by Douglas Hanahan of Ludwig Lausanne, Qiqun Zeng and Sadegh Saghafinia, both former members of his lab, and graduate student Agnieszka Chryplewicz, also outlines a signature of gene expression induced by the protein, called FMRP, which encompasses 156 different genes and foretells poor patient survival in a variety of cancer types.

The findings, reported in the journal Science, could with further development inform the selection of patients likely to benefit from immunotherapies and the development of new therapies for multiple types of cancer.

"Our study has detailed a previously unknown and apparently common mechanism by which malignant cells shut down anti-cancer immune responses," said Hanahan, a distinguished scholar at the Ludwig Institute for Cancer Research Lausanne Branch. "We have shown that the hyperexpression of FMRP, which we and others have previously linked to tumour progression, doesn't directly drive cancer cell proliferation and tumour growth. Rather, it supports the ability of malignant cells to manipulate the types and functional states of immune cells around them in a manner that very effectively subverts immune attack."

The neuro-developmental condition fragile X syndrome, which causes severe intellectual disability, has been linked to FMRP, a protein that is largely produced in neurons and is extensively explored as a potential risk factor. FMRP is a protein that regulates the translation of information from genes into proteins and aids in stabilizing messenger RNA readouts of genes in cells. Its significance in the development of cancer remained less obvious, though.

The researchers started by demonstrating that higher FMRP levels are present in a variety of tumour forms. They used CRISPR-Cas9 gene editing to remove FMR1, the gene that encodes FMRP, from mouse cancer cell lines in order to investigate its role in cancer.

Using animals with or without full immune systems, they created mouse models of pancreatic, colon, melanoma, and breast tumours using the altered cell lines and compared them to corresponding tumours that preserved their FMR1 genes.

All tumours developed uniformly in culture and in immunodeficient animals, but those lacking the FMR1 gene exhibited markedly slowed growth in mice with functioning immune systems. They were also significantly populated with cytotoxic and helper T cells, which are essential for the immune system's ability to fight cancer. Conversely, tumours carrying intact FMR1 genes advanced quickly and lacked anti-tumour T cells, earning the moniker "immune deserts."

The FMR1-deficient tumours stopped growing when T cells were removed from them, indicating that FMRP promotes tumour formation by influencing the immune response.

The scientists found that the FMRP-regulated gene-expression pathway in cancer cells triggers a number of immune evasion-supporting defensive mechanisms.

One of these is the release of substances that, among other things, encourage the induction of regulatory T cells, which inhibit the activity of cytotoxic T cells, or that rewire immune cells called macrophages so that they support the growth and survival of cancer cells rather than destroying them, largely by pacifying T cells.

In contrast, the absence of FMRP in cancer cells led to both the reversal of their immunosuppressive effects and the release of a substance that draws T lymphocytes. The FMRP-deficient cancer cells also secreted signals that told tumour-infiltrating macrophages to follow a stimulatory program that assisted in enlisting and activating T cells that are capable of destroying the tumour.

Despite the fact that FMRP expression alone is not a reliable prognostic biomarker for cancer outcomes, the researchers report that a signature of gene expression reflecting the regulatory network it induces reliably predicts relatively low survival odds in a variety of cancer types.

"We are hopeful that these discoveries can be translated into diagnostics and therapies of benefit to cancer patients, as the hallmark capability of cancers to circumvent immune responses underlies the resistance of many tumour types to immunotherapy," said Hanahan. To that point, the researchers have spun off a company named Opna Bio that is developing cancer drugs targeting FMRP and the pathways through which it exerts its effects.