Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.

Zeng, Qiqun; Saghafinia, Sadegh; Chryplewicz, Agnieszka; Fournier, Nadine; Christe, Lucine; Xie, Yu-Qing; Guillot, Jeremy; Yucel, Simge; Li, Pumin; Galván, José A; Karamitopoulou, Eva; Zlobec, Inti; Ataca, Dalya; Gallean, Fleuriane; Zhang, Peng; Rodríguez-Calero, José Antonio; Rubin, Mark; Tichet, Mélanie; Homicsko, Krisztian and Hanahan, Douglas (2022). Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion. Science, 378(6621), eabl7207. American Association for the Advancement of Science 10.1126/science.abl7207

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Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP's cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.

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