Hamilton, J. A. G. | Search bioRxiv

bioRxiv2024

The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.

bioengineering↗

bioRxiv2020

RIOK2 drives glioblastoma cell growth and proliferation by modulating MYC through the RNA-binding protein IMP3

Glioblastoma (GBM) is the most common primary malignant brain tumor and is resistant to current therapies. Here, using a combination of proteomic and genetic approaches in both Drosophila and human GBM models, we identify novel signaling effectors that act downstream of EGFR and PI3K signaling pathways, which drive GBM. Our results indicate that RIOK2, an atypical serine/threonine kinase, forms a complex with the RNA-binding protein, IMP3 (Imp in Drosophila), and that the dRIOK2/RIOK-Imp/IMP3 pathway is necessary for tumorigenesis. Furthermore, our results indicate that RIOK2 catalytic activity is important for neoplasia and recruits TORC2 to phosphorylate IMP3. Finally, the dRIOK2-Imp pathway regulates protein levels of dMyc, a known Imp target mRNA, and these key findings were recapitulated in human GBM models. Collectively, our data indicates that RIOK2 catalytic activity promotes the activation of TORC2 and recruitment of IMP3, which in turn, modulates MYC mRNA and protein levels to promote tumorigenesis.

cancer biology↗