Study Finds Common Targetable Mechanism Tumors Use to Suppress Immune Responses – ScienceDaily

Ludwig’s Cancer Research study revealed a single protein expressed at high levels by cancer cells across a wide range of malignancies that erects a multifaceted barrier to anticancer immune responses in mouse models of cancer and thus protects tumors from immune detection and destruction.

Led by Douglas Hanahan of Ludwig Lausanne, 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, that includes 156 distinct genes and predicts vulnerability. Patient survival across multiple types of cancer. The results published in the journal SciencesFurther development could inform the selection of patients who are likely to benefit from immunotherapies and the development of new such therapies for multiple types of cancer.

“Our study has detailed a previously unknown and apparently common mechanism by which malignant cells turn off anti-cancer immune responses,” said Hanahan, 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 malignant cells to manipulate the types and functional states of the immune cells around them in a way that effectively undermines immune attack.”

A protein primarily expressed in neurons, FMRP has been extensively studied as a factor whose loss of expression during embryonic development is associated with the neurodevelopmental disorder fragile X, which causes severe intellectual disability. Functionally, FMRP is known to help stabilize messenger RNA reads of genes in cells and regulate the translation of that information into proteins. But its role in the development of cancer has been less clear.

The researchers set out to demonstrate that FMRP levels are elevated across multiple types of tumors. To examine its function in cancer, they applied 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 generate mouse models of pancreatic, colon, melanoma, and breast tumors and compared them to matching tumors that retained their FMR1 genes, using mice that had or lacked healthy immune systems.

While all tumors grew similarly in culture and immunodeficient mice, those lacking the FMR1 gene were severely impaired in mice with competent immune systems. It is also highly infiltrated by helper and cytotoxic T cells, which play a key role in anticancer immunity. On the other hand, those with intact FMR1 genes progressed aggressively and were, in comparison, 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 effect on the immune response.

The researchers discovered that an FMRP-regulated gene expression program in cancer cells activates multiple defense mechanisms that support immune evasion.

Among these are the release of factors that differentially enhance the induction of regulatory T cells—which suppress the activity of cytotoxic T cells—or the reprogramming of immune cells known as macrophages into a functional state in which they support cancer growth and survival. rather than destroying them, largely by quieting down the T cells.

Meanwhile, loss of FMRP in cancer cells not only reversed their immunosuppressive effects, but also resulted in their secretion of a factor that attracts T cells. In addition, FMRP-deficient tumor cells released signals that were directed to tumor-infiltrating macrophages to adopt a stimulatory program that assists in the recruitment and activation of tumor-suppressing T cells.

While FMRP expression by itself is not a reliable predictive biomarker for cancer outcome, researchers report that a gene expression signature that reflects the regulatory network it induces consistently predicts relatively poor odds of survival in multiple types of cancer.

“We hope these discoveries will translate into useful diagnostics and treatments for cancer patients, since the hallmark of cancers to circumvent immune responses underlies the resistance of many types of tumors to immunotherapy,” Hanahan said. To this point, the researchers have set up 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 Foundation, and Goran Grosskopf.

Hanahan is also Professor Emeritus and former Director of the Swiss Institute for Experimental Cancer Research (ISREC) at the Swiss Federal Institute of Technology Lausanne (EPFL).

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