Ludwig Cancer Research team have found a single protein that is produced at high levels by cancer cells across a wide spectrum of malignancies. In animal models of cancer, this protein builds a complex barrier to anti-cancer immune responses, shielding tumours from immune identification and killing.
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, known as FMRP, that encompasses 156 different genes and predicts poor patient survival in a variety of cancer types.
The findings, published in the journal Science, might help guide the selection of patients who will benefit from immunotherapies and the development of novel medicines for a variety of cancers in the future.
“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.”
Fragile X syndrome, a neurodevelopmental disorder that causes severe intellectual impairment, has been related to FMRP, a protein that is mostly synthesised in neurons and is being studied as a possible risk factor. FMRP is a protein that controls gene-to-protein translation and assists in the stabilisation of messenger RNA readouts in cells. However, its role in the genesis of cancer remained unclear.
The researchers began by establishing that greater FMRP levels may be seen in a range of tumour types. In order to examine the role of FMRP in cancer, they employed CRISPR-Cas9 gene editing to eliminate FMR1, the gene that encodes FMRP, from mouse cancer cell lines.
They constructed mouse models of pancreatic, colon, melanoma, and breast tumours using the changed cell lines and compared them to equivalent tumours that retained their FMR1 genes using animals with or without intact immune systems.
All tumours expanded evenly in culture and in immunocompromised animals, but those missing the FMR1 gene grew at a significantly slower rate in mice with functional immune systems. They were also densely packed with cytotoxic and helper T cells, both of which are critical for the immune system’s capacity to combat cancer. Tumors with intact FMR1 genes, on the other hand, progressed swiftly and lacked anti-tumor T cells, gaining the term “immune deserts.”
When T cells were removed from FMR1-deficient tumours, they stopped growing, demonstrating that FMRP promotes tumour growth via modulating the immune response.
The FMRP-regulated gene-expression pathway in cancer cells activates a range of immune evasion-supporting defence mechanisms, according to the researchers.
One of these is the release of substances that, among other things, promote the induction of regulatory T cells, inhibit the activity of cytotoxic T cells, or rewire immune cells known as macrophages so that they support the growth and survival of cancer cells rather than destroying them, primarily through the pacification of T cells.
The lack of FMRP in cancer cells, on the other hand, resulted in the reversal of their immunosuppressive effects as well as the production of a chemical that attracts T lymphocytes.
The FMRP-deficient cancer cells also produced signals that instructed tumor-infiltrating macrophages to engage in a stimulatory programme that aided in the recruitment and activation of T cells capable of eliminating the tumour.
Despite the fact that FMRP expression alone is not a good predictive biomarker for cancer outcomes, the researchers reveal that a gene expression profile representing the regulatory network it produces accurately predicts relatively low survival probabilities in a range 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 end, the researchers founded Opna Bio, which is researching cancer therapies that target FMRP and the mechanisms via which it works