Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion
- Zeng, Qiqun1
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Saghafinia, Sadegh1
- Chryplewicz, Agnieszka1
- Zangger, Nadine1
- Christe, Lucine2
- Christie, Lucine3
- Xie, Yu-Qing4
- Guillot, Jeremy1
- Yucel, Simge1
- Li, Pumin1
- Galván, José A.3
- Karamitopoulou, Eva3
- Zlobec, Inti3
- Ataca, Dalya1
- Gallean, Fleuriane1
- Zhang, Peng5
- Xie, Yuqing6
- Rodriguez-Calero, José Antonio7
- Rubin, Mark7
- Tichet, Mélanie1
- Homicsko, Krisztian8
- Hanahan, Douglas1
- 1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
- 2. Institute of Pathology, University of Bern
- 3. Institute of Pathology, University of Bern, Bern, Switzerland
- 4. Institute of Bioengineering, School of Engineering, Swiss Federal Institute of Technology Lausanne
- 5. Children's National Medical Center, Center for Cancer and Immunology Research, Washington D.C., United States
- 6. Institute of Bioengineering, School of Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
- 7. Department for BioMedical Research, University of Bern, Bern, Switzerland
- 8. Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
Description
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), 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.