A Ludwig Cancer Research study has revealed a single protein expressed at high levels by cancer cells in a wide range of malignant tumors that erects a multifaceted barrier to anti-cancer immune responses in mouse models of cancer and thereby protects tumors from detection and immune destruction.
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 protein-induced gene expression signature, named FMRP, which encompasses 156 distinct genes and predicts poor patient survival in multiple cancer types. The results, reported in the journal Sciencecould ultimately shed light on the selection of patients likely to benefit from immunotherapies and the development of new therapies of this type for multiple types of cancer.
“Our study detailed a previously unknown and apparently common mechanism by which malignant cells shut down anti-cancer immune responses,” said Hanahan, a senior researcher at the Ludwig Institute for Cancer Research, Lausanne Branch. “We have shown that overexpression of FMRP, which we and others have previously linked to tumor progression, does not directly lead to cancer cell proliferation and tumor growth. Rather, it supports the ability of cells malignancies to manipulate the types and functional states of the immune cells around them in a way that very effectively subverts the immune attack.”
A protein mainly expressed in neurons, FMRP has been widely studied as a factor whose loss of expression during embryogenesis is associated with the neurodevelopmental disorder of fragile X syndrome, responsible for severe intellectual disability. . Functionally, FMRP is known to help stabilize 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 started by showing that FMRP levels are elevated in several tumor types. To examine its function in cancer, they applied CRISPR-Cas9 gene editing to delete FMR1, the gene that codes for FMRP, in mouse cancer cell lines. They then used the modified cell lines to generate mouse models of pancreatic, colon, melanoma and breast tumors and compared them to corresponding tumors that retained their FMR1 genes, using mice that either had or had not. no intact immune system.
While all tumors grew equally 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, progressed aggressively and were in comparison to so-called “immune deserts” – devoid of anti-tumor T cells. When T cells were removed from FMR1-deficient tumors, they resumed growth, suggesting that FMRP supports tumor progression through its effects on the immune response.
The researchers found that the FMRP-regulated gene expression program in cancer cells activates multiple defense mechanisms that promote immune evasion.
Among these is the release of 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 cancer growth and survival. cells instead of destroying them, largely by pacifying T cells.
Loss of FMRP in cancer cells, meanwhile, not only reversed their immunosuppressive effects, but also induced their secretion of a factor that attracts T cells. that instructed tumor-infiltrating macrophages to adopt a stimulation program that helped recruit and activate tumor-killing T cells.
Although FMRP expression itself is not a reliable prognostic biomarker for cancer outcomes, researchers report that a gene expression signature reflecting the regulatory network it induces consistently predicts relatively high survival odds. low in several types of cancer.
“We hope these findings can translate into diagnostics and therapies that benefit cancer patients, because the characteristic ability of cancers to evade immune responses underlies the resistance of many tumor types to immunotherapy,” Hanahan said. At this point, the researchers created a company called Opna Bio that is developing cancer drugs that target FMRP and the pathways through which it exerts its effects.
The research was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Biltema Foundation, the Cancera and Paulsson and Goran Grosskopf Foundations.
Hanahan is also Emeritus Professor and former Director of the Swiss Institute for Experimental Cancer Research (ISREC) at the Swiss Federal Institute of Technology Lausanne (EPFL).