Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

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.

Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy: an in silico experiment

“…As TILs frequency and PD1/PDL1 expression are not sufficient to predict response efforts have been concentrated on identifying additional predictive markers. The cellular composition of the TME, the RNA gene expression profiling of T cells, aberrant chemokine and cytokine expression (i.e., CCL7, IL-33), and mutational tumor burden appear to play an important role in determining the efficacy of check point inhibitors-based immunotherapies 50 , 51 , 60 .…”

PAIP1 regulates expression of immune and inflammatory response associated genes at transcript level in liver cancer cell

“…This results indicated that that PAIP1 may play a role as immune regulator in liver cancer. In addition, a recently study reported that aberrant hyperexpression of the RNA binding protein FMRP mediates immune evasion of tumor cell ( Zeng et al, 2022 ). We speculated that PAIP1 may play a role as immune regulator and promote the immune evasion of liver cancer cell, which partially interpreted that high PAIP1expression had shorter overall survival.…”

Targeting FMRP: A new window for cancer immunotherapy

“…A recent study published in Science by Zeng et al described a novel component, fragile X mental retardation 1 protein (FMRP), that can mediate tumor immune escape, which provides a new insight for immunotherapy (Figure 1 ). 3 …”

“…A recent study published in Science by Zeng et al described a novel component, fragile X mental retardation 1 protein (FMRP), that can mediate tumor immune escape, which provides a new insight for immunotherapy (Figure 1). 3 Highly expressed FMRP in neural cells plays a vital role in proper synaptic plasticity and architecture. FMRP inactivation by a triplet nucleotide repeat expansion leads to a neurodevelopmental disorder called fragile X syndrome.…”