A study by Ludwig Cancer Research has revealed a single protein that is expressed at high levels by cancer cells in a wide range of malignancies, which creates a multifaceted barrier to anti-cancer immune responses in mouse models of cancer and thereby protects tumors from immune detection and destruction.
The study, led by Douglas Hanahan of Ludwig Lausanne, two former scientists in his lab, Cijun Zeng and Sadegh Sagafinia, and graduate student Agnieszka Hryplewicz, also describes features of gene expression caused by a protein called FMRP, which spans 156 different genes and predicts poor patient survival in a variety of cancers. The findings are reported in the journal Sciencemay, with further development, inform the selection of patients likely to benefit from immunotherapy and the development of new treatments for various cancer types.
“Our study details a previously unknown and apparently widespread mechanism by which malignant cells turn off anti-cancer immune responses,” said Hanahan, a distinguished scientist at the Lausanne branch of the Ludwig Cancer Institute. “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 malignant cells 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 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 reading of messenger RNA genes in cells and regulates the translation of this information into proteins. But its role in cancer progression was less clear.
The researchers began by showing that FMRP levels are elevated in different types of tumors. To study its function in cancer, they used CRISPR-Cas9 gene editing to delete FMR1, the gene that encodes 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 corresponding tumors that had retained their FMR1 genes, using mice that had or did not have an intact immune system.
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. On the other hand, those with intact FMR1 genes progressed aggressively and, by comparison, were 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 by influencing the immune response.
The researchers found that the program of gene expression regulated by FMRP in cancer cells activates several defense mechanisms that support immune evasion.
These include 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, to a functional state in which they support the growth and survival of cancer cells instead of destroying them , mainly through quiescence of T cells.
Meanwhile, loss of FMRP in cancer cells not only altered their immunosuppressive effects, but also caused them to secrete a factor that attracts T cells. In addition, FMRP-deficient cancer cells emitted signals that instructed tumor-infiltrating macrophages to adopt a stimulatory program that helped recruit and activate tumor-killing T cells.
Although FMRP expression itself is not a reliable prognostic biomarker for cancer outcome, the researchers report that a gene expression signature that reflects the regulatory network it induces consistently predicts relatively poor survival in various types of cancer.
“We hope that these discoveries can be translated into diagnostics and therapies useful for cancer patients, as the characteristic ability of cancer to evade immune responses underlies the resistance of many types of tumors to immunotherapy,” Hanahan said. Until now, the researchers have spun off a company called Opna Bio, which is developing cancer drugs that target FMRP and the pathways through which it exerts its effects.
The study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Biltema Foundation, the Cancera and Paulsson Foundations, and Goran Groskopf.
Hanahan is also professor emeritus and former director of the Swiss Institute for Experimental Research on Cancer (ISREC) at the Swiss Federal Institute of Technology Lausanne (EPFL).