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A single protein erects a multifaceted barrier to anti-tumor immunity in mouse models

Douglas Hanahan

A study led by Ludwig Lausanne’s Douglas Hanahan, alumni Qiqun Zeng and Sadegh Saghafinia, and graduate student Agnieszka Chryplewicz revealed a single protein hyperexpressed by cancer cells across a broad range of malignancies that erects a multifaceted barrier to anti-tumor immune responses in mouse models. It also captured a signature of gene expression induced by the protein, FMRP, that encompasses 156 distinct genes and predicts poor patient survival. A protein primarily expressed in neurons, FMRP has been extensively studied as a factor whose loss of expression during embryogenesis is associated with the neuro-developmental disorder fragile X syndrome. The researchers generated models of pancreatic, colon, melanoma and breast tumors lacking the gene for FMRP using immunocompetent and immunocompromised mice and compared them to corresponding tumors that retained the gene. Their studies using these models, reported in November in Science, showed that the gene-expression program regulated by FMRP in cancer cells promotes the induction of regulatory T cells—which suppress cytotoxic T cells—and reprograms macrophages into a functional state in which they support the growth and survival of cancer cells. The loss of FMRP in cancer cells not only reversed these effects but also induced their secretion of factors that support vigorous antitumor immune responses mediated by cytotoxic T cells and macrophages. The researchers have co-founded a company, Opna Bio, that is developing cancer drugs based on these findings.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion
Science, 2022 November 17

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