1. Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.
- Author
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Zeng Q, Saghafinia S, Chryplewicz A, Fournier N, Christe L, Xie YQ, Guillot J, Yucel S, Li P, Galván JA, Karamitopoulou E, Zlobec I, Ataca D, Gallean F, Zhang P, Rodriguez-Calero JA, Rubin M, Tichet M, Homicsko K, and Hanahan D
- Subjects
- Animals, Humans, Mice, Chemokine CCL7 metabolism, Interleukin-33, Protein S metabolism, Fragile X Mental Retardation Protein genetics, Fragile X Mental Retardation Protein metabolism, Immune Evasion, Neoplasms immunology, Immune Tolerance
- 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.
- Published
- 2022
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