Immune checkpoint blockade (ICB) therapy has shown promising clinical efficacy in cancer treatment, but only a subset of patients experience significant therapeutic responses. Tumor cells respond to internal and external stresses, such as hypoxia and nutrient deprivation, by activating the unfolded protein response (UPR) in the tumor microenvironment. This response helps maintain homeostasis, promoting malignant progression, chemotherapy resistance, and immune escape. In this study, single-cell RNA sequencing (scRNA-seq) data from non-small cell lung cancer (NSCLC) patients treated with ICB revealed upregulation of thioredoxin (TXN) expression in the epithelial tissues of LUAD (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma) patients with minimal pathological remission. High TXN expression was also associated with "cold tumors," characterized by a lack of T cells and low levels of chemokine receptors and immunomodulators. Experimental results showed that TXN was highly expressed in NSCLC tissues, and its knockdown significantly inhibited the proliferation and migration of A549 and SK-MES-1 cells. Furthermore, TXN knockdown enhanced T-cell-mediated cytotoxicity against these tumor cells, suggesting that TXN contributes to immune escape in NSCLC by promoting tumor cell proliferation and migration while inhibiting immune killing. Notably, TXN knockdown also upregulated CD40 expression, indicating that TXN may regulate immune escape in lung cancer through CD40 modulation.
© 2025. The Author(s).

Urine-derived stem cells (USCs) have been widely researched as a novel cell source for stem cell therapy, but their immunomodulatory characteristics remain to be investigated. This study aimed to characterize the immunomodulatory properties of human USCs.
Human USCs were isolated from fresh voiding urine samples from healthy male donors and expanded. Their cell surface markers were characterized by flow cytometry analysis and the telomerase activities for several USCs clones were determined. The immunosuppressive potential of USCs was evaluated by the performing the mixed lymphocyte reaction (MLR) [co-culture with peripheral blood mononuclear cells (PBMNCs)] and natural killer cells (NK) cytotoxicity assay. USCs cytokines release profile was determined by using human cytokine proteome array.
USCs exhibited high cell surface expression of embryonic/mesenchymal stem cells (MSCs) markers CD29, CD44, CD54, CD73, CD90, CD146, and CD166, while lacked expression of hematopoietic stem cell markers CD11, CD14, CD19, CD31, CD34, CD45, B cell marker CD79, and co-stimulatory factors CD80 and CD86, thus, exhibiting the phenotype of MSCs. MLR indicated that USCs significantly inhibited the proliferation of PBMNCs, as compared to that of the human smooth muscle cells (SMCs). In cell cytotoxicity assays, NK cells displayed less cytotoxicity against USCs than against bone marrow mesenchymal stem cells (BMSCs) and SMCs. Furthermore, upon PBMNCs stimulation, USCs secreted higher levels of immunomodulatory cytokines, including IL-6, IL-8, MCP-1, RANTES, GROα, and GM-CSF, compared to those of BMSCs, especially when directly contact mix-culture with PBMNCs.
USCs secreted immunoregulatory cytokines and possessed immunomodulatory properties, comparable to those of BMSCs.
2021 Translational Andrology and Urology. All rights reserved.

Previously, using FREP-MS, we identified a protein complex including eight proteins that specifically bind to the functional SNP (fSNP) rs6032664 at a CD40 locus associated with autoimmune diseases. Among these eight proteins, four are ribosomal proteins RPL26, RPL4, RPL8, and RPS9 that normally make up the ribosomal subunits involved in the cellular process of protein translation. So far, no publication has shown these ribosomal proteins function as transcriptional regulators. In this work, we demonstrate that four ribosomal proteins: RPL26, RPL4, RPL8, and RPS9 are bona fide CD40 transcriptional regulators via binding to rs6032664. In addition, we show that suppression of CD40 expression by RPL26 RNAi knockdown inactivates NF-κB p65 by dephosphorylation via NF-κB signaling pathway in fibroblast-like synoviocytes (FLS), which further reduces the transcription of disease-associated risk genes such as STAT4, CD86, TRAF1 and ICAM1 as the direct targets of NF-κB p65. Based on these findings, a disease-associated risk gene transcriptional regulation network (TRN) is generated, in which decreased expression of, at least, RPL26 results in the downregulation of risk genes: STAT4, CD86, TRAF1 and ICAM1, as well as the two proinflammatory cytokines: IL1β and IL6 via CD40-induced NF-κB signaling. We believe that further characterization of this disease-associated TRN in the CD40-induced NF-κB signaling by identifying both the upstream and downstream regulators will potentially enable us to identify the best targets for drug development.