A study by Ludwig Cancer Research has revealed that a single protein expressed at high levels by cancer cells in a broad range of malignancies erects a multifaceted barrier to anti-cancer immune responses in mouse models of cancer and thus protects tumors from detection and destruction immune.
Led by Ludwig Lausanne’s Douglas Hanahan, 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, called FMRP, which includes 156 distinct genes and predicts poor patient survival in several cancer types. The results, reported in the journal Sciencecould with further development inform the selection of patients who could benefit from immunotherapies and the development of new such therapies for multiple types of cancer.
“Our study detailed a previously unknown and seemingly common mechanism by which malignant cells disrupt anti-cancer immune responses,” said Hanahan, Distinguished Scientist at the Ludwig Institute for Cancer Research in Lausanne. “We demonstrated that overexpression of FMRP, which we and others have previously linked to tumor progression, does not directly drive tumor 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 very effectively subverts the immune attack.”
A protein expressed primarily in neurons, FMRP 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 help stabilize the messenger RNA readouts of genes in cells and regulate the translation of that information into proteins. But its role in cancer progression was less clear.
The researchers began by showing that FMRP levels are elevated in multiple types of cancers. To examine 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 generate mouse models of pancreatic, colon, melanoma and breast cancers and compared them to matched tumors that retained their FMR1 genes, using mice that had or did not have intact immune systems.
While all tumors grew similarly in culture and in immunodeficient 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 anticancer immunity. Those with intact FMR1 genes, on the other hand, progressed aggressively and were so-called “immune deserts” by comparison – devoid of anticancer 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 support immune evasion.
Among these are 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 where they support growth and survival of cancer cells instead of destroying them, largely by pacifying the T cells.
Loss of FMRP in the cancer cells, meanwhile, not only reversed their immunosuppressive effects, but also induced their secretion of T-cell attractant factor. In addition, FMRP-deficient cancer cells released signals that instructed the tumor-infiltrating macrophages to adopt a stimulation schedule that would help recruit and activate tumor-killing T cells.
While FMRP expression itself is not a reliable prognostic biomarker for cancer outcomes, researchers report that a gene expression signature that reflects the regulatory network it induces consistently predicts relatively poor odds of survival across multiple cancer types.
“We hope these findings can be translated into diagnostics and beneficial therapies for cancer patients, as the characteristic ability of tumors to bypass immune responses underlies the resistance of many tumor types to immunotherapy,” Hanahan said. At that point, the researchers spun off 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 Foundations and Goran Grosskopf.
Hanahan is also professor emeritus and former director of the Swiss Institute for Experimental Cancer Research (ISREC) within the Federal Institute of Technology Lausanne (EPFL).