FMRP Depletion Reprograms an Immunosuppressive Microenvironment

Cancers often rely on an immunosuppressive microenvironment to promote tumor progression, highlighting the need to understand key regulators of immune evasion. Previous studies have reported the frequent upregulation of the fragile X mental retardation protein (FMRP, encoded by the gene FMR1) in many human tumors, but the potential tumor-promoting functions of this RNA binding protein remain incompletely understood. To further elucidate the role of FMRP in tumor progression, Zeng, Saghafinia, Chryplewicz, and colleagues used CRISPR–Cas9 to knock out Fmr1 in murine cell line models of pancreatic, colon, skin, and breast cancer. Whereas Fmr1-knockout cancer cells behaved similarly to control cancer cells when injected into immunodeficient mice, injection of Fmr1-knockout cancer cells into immunocompetent mice led to relatively reduced tumor growth, decreased metastatic tumor burden, and prolonged survival, indicating the involvement of the immune system in mediating these effects. Indeed, while control tumors exhibited minimal T-cell infiltration, CD4⁺ and CD8⁺ T cells were abundant in Fmr1-knockout tumors and essential for the attenuated Fmr1-knockout phenotypes, supporting the role of FMRP in suppressing adaptive immunity. Single-cell RNA sequencing analysis paired with cell–cell communication inference revealed substantial differences in lymphocyte representation in Fmr1-knockout pancreatic tumors as a result of FMRP-mediated changes in cancer cell expression of the cytokines CCL7 (increased) and IL33 (decreased), leading to enhanced infiltration of CD8⁺ effector T cells and decreased abundance of regulatory CD4⁺ T cells, respectively. In addition to these effects on the adaptive immune system, control cancer cells reprogrammed macrophages into an M2-like immunosuppressive phenotype through the expression of PROS1 and the release of exosomes, whereas macrophages in coculture with Fmr1-knockout cancer cells retained immunostimulatory M1-like features. Moreover, a transcriptional signature of FMRP-regulated genes in cancer was associated with reduced overall survival and CD8⁺ T-cell infiltration in patient samples across multiple cancer types. Overall, these findings identify multiple transcriptional targets downstream of FMRP activity and demonstrate how FMRP promotes an immunosuppressive tumor microenvironment.

Zeng Q, Saghafinia S, Chryplewicz A, Fournier N, Christe L, Xie YQ, et al. Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion. Science 2022;378:eabl7207.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.