FMRP mediates immune evasion in mouse tumors

Genetic inactivation of the neuronal fragile X mental retardation protein (FMRP) in cancer cells resulted in reduced growth and increased T cell vulnerability in mouse tumors, researchers report. Many human cancers develop the ability to evade the adaptive immune system, rendering them resistant to immunotherapeutic treatments. Therapeutic strategies designed to disrupt these barriers to immune vulnerability have shown promising results in some patients and cancers. However, most patients do not respond to immunotherapies or only experience limited or short-term benefits. These common outcomes underscore an urgent need to better understand the cellular and molecular mechanisms underlying the immune responses to cancer in order to develop more effective treatments. To address this need, Qiqun Zeng and colleagues investigate the potential role of FMRP, an RNA binding translational regulatory protein commonly associated with the stability and translation of neuronal RNAs. While previous research has also implicated FMRP in tumor progression, little is known about its functional roles in cancer and immunoregulation. By genetically modulating the expression of the FMRP gene in cancer cells in mice, Zeng et al. discovered that immune evasion often involves frequent, abnormal expression of FMRP in solid tumors, which has the effect of repressing immune attack in cancer cells. Inactivating FMRP expression in mouse tumor cells resulted in reduced tumor growth and greater susceptibility to attack by T cells, leading to enhanced survival of the mice. The authors suggest that, mechanistically, FMRP creates a barrier to the recruitment and expansion of T lymphocytes within tumors, which allows them to evade immune destruction. “The widespread expression of FMRP in solid tumors, concomitant with induction of its cancer regulatory network, constitutes a previously unappreciated mechanism whereby tumors evade immune destruction,” write the authors.