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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. Description FMRP and tumor immunity Many tumors have developed mechanisms rendering them resistant to attack and destruction by the immune system. Zeng et al. report that fragile X mental retardation protein (FMRP) is highly expressed in human cancers, and they propose that it is involved in antitumor immunity. FMRP is best known as an RNA-binding protein that regulates the stability and translation of neuronal RNAs. By genetically inactivating the FMRP gene in mouse cancer cells, the researchers found that FMRP-deficient tumors had reduced growth and were more susceptible to attack by T lymphocytes. Tumor cells lacking FMRP showed remodeling of the tumor microenvironment, macrophage polarization, and upregulation of the chemokines involved in effector CD8+ T cell recruitment. —PNK Genetic inactivation of the neuronal fragile X mental retardation protein increased CD8+ T cell infiltration and reduced the growth of mouse tumors. INTRODUCTION Cancer biology and therapy have been transformed by knowledge about immunoregulatory mechanisms that govern adaptive immunity. Although some forms of treatment resistance are related to the intentionally transitory operations of the adaptive immune system, others reflect more subtle requirements to modulate the immune system in different contexts. In this work, we identified an immunoregulatory mechanism involving the neuronal RNA binding protein fragile X mental retardation protein (FMRP), which broadly regulates protein translation and mRNA stability and is aberrantly up-regulated in multiple forms of cancer. RATIONALE This study was motivated by reports that cancer cells naturally overexpressing FMRP, whose loss of expression in developing neurons causes cognitive defects, were invasive and metastatic. We investigated the expression of FMRP in human tumors, further assessed its tumor-promoting functions in mouse models of cancer, and evaluated its association with prognosis for human cancer patients. RESULTS When human tumor tissue microarrays were immunostained for expression of FMRP, a majority of tumors expressed FMRP, whereas cognate normal tissues did not. To investigate the functional significance of this broad up-regulation, the FMR1 gene was ablated through CRISPR-Cas9 gene editing (FMRP-KO, where KO indicates knockout) in mouse cancer cell lines that were inoculated into both immunodeficient and syngeneic immunocompetent mice to establish tumors in parallel with wild-type (WT) FMRP-expressing cell lines. Mice bearing FMRP-KO tumors had similar survival compared with isogenic WT tumors in immunodeficient hosts, indicating that FMRP was not involved in stimulating tumor growth per se. By contrast, tumor growth was impaired and survival extended in immunocompetent hosts, implicating the adaptive immune system. Indeed, FMRP-expressing WT tumors were largely devoid of T cells, whereas FMRP-KO tumors were highly inflamed. Depletion of CD8 and CD4 T cells restored tumor growth and reduced survival, implicating FMRP in immune evasion in WT tumors. WT and FMRP-KO tumors were profiled by single-cell RNA sequencing, revealing marked differences in genome-wide transcription and abundance of cancer cells, macrophages, and T cells. To elucidate the effects of this multifaceted regulatory protein, we performed several functional perturbations, revealing that: FMRP-expressing cancer cells produce the chemokine interleukin-33 (IL-33), which induces regulatory T cells, as well as tumor-secreted protein S (PROS1) ligand and exosomes that elicit tumor-promoting (M2) macrophages. Both cell types are immunosuppressive, collectively contributing to the barrier against T cell attack. By contrast, FMRP-KO cancer cells down-regulate all three factors and up-regulate C-C motif chemokine ligand 7 (CCL7), which helps recruit and activate T cells. Additionally, immunostimulatory macrophages develop in this context that express three proinflammatory chemokines—CCL5, CXCL9, and CXCL10—which cooperate with CCL7 in recruiting T cells. Finally, neither FMR1 mRNA nor FMRP protein levels were sufficient to predict outcomes in cohorts of cancer patients. Recognizing FMRP’s function as an RNA binding protein that modulates mRNA stability and hence levels in transcriptome datasets, a gene signature reflecting FMRP’s cancer regulatory activity (involving 156 genes) was developed by comparing FMRP-expressing versus FMRP-deficient cancer cells, both in culture and within tumors. Our FMRP cancer activity signature was prognostic for survival across multiple human cancers; anticorrelated with the intensity of T cell infiltration in different tumor types, consistent with FMRP’s immunosuppressive effects; and was associated with comparatively poor responses to immune checkpoint inhibitors and immune-dependent chemotherapy in selected cohorts. CONCLUSION FMRP is revealed as a regulator of a network of genes and cells in the tumor microenvironment that contribute to the capability of tumors to evade immune destruction. FMRP enables tumors to evade being attacked by the immune system. Up-regulated FMRP expression and activity are involved in an immunosuppressive program in cancer cells (upper left) that renders tumors impenetrable, creating so-called immune deserts (upper right). By contrast, its absence is associated with a reprogrammed tumor microenvironment that recruits and activates T lymphocytes, producing inflamed tumors, including CD8 T cells (red immunostain; lower right) with consequently beneficial immune destruction. Tregs, regulatory (immunosuppressive) T cells.