Biology subjects

Koss, B.

Publications and source records attributed to Koss, B..

3 recordsLinked to original sources

bioRxiv2026

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation to an exhausted state. In healthy tissues, tissue-resident memory T cells (TRM) maintain protection for years, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally-exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins in spite of functional proteasome activity. Enforced expression of these ligases by TIL preserved stem-like TCF1+ populations and improved anti-tumor function, whereas their knockout impaired TIL and altered T cell differentiation in acute infection. Sustained ligase expression rescued accumulation of unfolded proteins in TIL and improved immunotherapy outcome in preclinical models, highlighting the critical role of proteostasis in TIL function and identifying new avenues for advancing cancer immunotherapy.

immunology↗

bioRxiv2025

DNA-PKcs governs LAT-dependent signaling in CD4+ and CD8+ T cells

Formation of the immune synapse (IS) following T cell antigen recognition includes recruitment of the Linker for Activation of T cells (LAT). Once at the IS, LAT tyrosines are phosphorylated allowing it to serve as a scaffold for formation of the "signalosome", a multiprotein complex that drives TCR signaling. Here, we show that upon T cell activation, DNA dependent protein kinase catalytic subunit (DNA-PKcs) interacts with LAT and localizes to the IS. Inhibition of DNA-PKcs diminishes LAT localization at the IS. We identified two LAT serines phosphorylated by DNA-PKcs, S224 and S241, that impact LAT tyrosine phosphorylation, protein binding, and cytokine production. Using our mouse model designed to delete DNA-PKcs expression within mature CD4+ or CD8+ T cells, we show loss of DNA-PKcs results in T cells unable to control tumor growth or induce allogeneic graft rejection. These data bring to the forefront DNA-PKcs as a pivotal protein in T cell function.

immunology↗

bioRxiv2022

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for continued investigation of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system spurring interest in its use as a therapeutic target for immune-related diseases. In murine models of autoimmune disease including asthma and rheumatoid arthritis, treatment with small molecule DNA-PKcs inhibitors, which are in clinical trials for cancer therapy, decreased disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection and extended graft survival in a murine allogenic skin graft rejection model. These in vivo studies suggest the therapeutic use of DNA-PKcs inhibitors for autoimmune and T cell-mediated disorders. In this study, we sought to further characterize the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that pharmacological inhibition of DNA-PKcs abrogated activation of murine and human CD4+ and CD8+ T cells as evident by reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and proliferation of anti-CD3/CD28 activated CD4+ and CD8+ T cells as well as peptide-stimulated OTI-CD8+ T cells. This reduced the ability of OTI-CD8+ T cells to kill cancer cells and the expression of IFN{gamma} and the cytotoxic genes eomes, perforin and granzyme B. These results suggest a novel role for DNA-PKcs in early T cell activation. Furthermore, our data support the therapeutic potential of DNA-PKcs inhibitors on diseases of immune dysregulation.

immunology↗