Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion
Qiqun Zeng, Sadegh Saghafinia, Agnieszka Chryplewicz, Nadine Fournier, Lucine Christe, Yuqing Xie, Jérémy Guillot, Simge Yucel, Pumin Li, José A. Galván, Eva Karamitopoulou, Inti Zlobec, Dalya Ataca, Fleuriane Gallean, Peng Zhang, Antonio Rodríguez-Calero, Mark A. Rubin, Mélanie Tichet, Krisztián Homicskó, Douglas Hanahan
Abstract
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.