Unraveling the Impact of Extracellular Vesicle-Loaded FXR1 mRNA on Re-educating Cancer Microenvironment - Abstract This study focuses on ovarian cancer, a significant cause of mortality among women with gynecological malignancies. The tumor microenvironment (TME) plays a crucial role in tumorigenesis, and our research characterize the involvement of fragile X mental retardation autosomal related protein-1 (FXR1), an RNA binding protein, in ovarian cancer progression. FXR1 is highly expressed in ovarian cancer due to the amplification of chromosome locus 3q26 encompass FXR1. We discovered that FXR1 mRNA is encapsulated and enriched within extracellular vesicles (EVs) produced by tumor cells. We hypothesize that specific nucleotide elements in FXR1 mRNA interact with TSG101, which is an integral part of EV for encapsulating FXR1 into EVs. We further demonstrated that FXR1 mRNA encapsulation into EVs are transported from tumor cells to the cells in tumor microenvironment. We observed high level of FXR1-EVs in tumor resident macrophages due to the phagocytic abilities of macrophages. Our recent work showed that FXR1 promotes the translation of oncogenic proteins like cMYC in cancer cells. However, the impact of FXR1 in macrophages and other tumor associated cells have not been characterized. Based on our data, we hypothesize that FXR1 upregulation in macrophages is required for an overall increase in the translation (protein synthesis) of several mRNAs that are important for macrophage polarization favorable for cancer progression. We also hypothesize that FXR1 promotes the polarization of M2 macrophages, which exhibits tumor associated macrophage (TAM) characteristics and express high levels of immune checkpoint proteins. Consequently, FXR1-EVs production and its incorporation in macrophages resulted in T-cell inactivation and T-cell exhaustion. Unlike melanoma, lung cancer, and bladder cancer, ovarian cancer exhibits poor responsiveness to immunotherapy, categorizing it as a less immunogenic or 'cold' tumor. Taken together, our hypothesis posits that FXR1-EVs play a significant role in rendering ovarian cancer less immunogenic. Therefore, elucidating the mechanism by which FXR1-containing extracellular vesicles (EVs) selectively target macrophages, modulate their functions, and inhibiting this process could offer novel opportunities to sensitize immunotherapy for cancer.
