IJMS, Vol. 27, Pages 1511: Prostate Cancer: Dissecting Novel Immunosuppressive Mechanisms Through Context-Specific Transcriptomic Programs and MDSC Cells
International Journal of Molecular Sciences doi: 10.3390/ijms27031511
Authors:
Pedro Reyes Martinez
Erick Sierra Diaz
Fabiola Solorzano Ibarra
Jorge Raul Vazquez Urrutia
José de Jesús Guerrero García
Martha Cecilia Téllez Bañuelos
Julio Enrique Castañeda Delgado
Karina Sanchez Reyes
Pablo Cesar Ortiz Lazareno
Prostate cancer remains largely refractory to immunotherapy, implying the existence of context-specific immune landscape programs that diverge between circulation and tumor. Here, we integrate bulk RNA sequencing from three cohorts (patient peripheral mononuclear cells, primary prostate tissue, and biochemical-recurrence tumors) with multiparameter flow cytometry, unsupervised UMAP/T-REX (Tracking Responders Expanding) mapping, and de novo discovery of long non-coding RNAs (lncRNAs) to characterize context-specific immunoregulation. Patient PBMCs revealed a coherent IL-1/TNF/IL-17 inflammatory architecture with strong chemotactic programs and an unexpected neutrophil-like signal despite density-gradient isolation, consistent with low-density PMN-MDSCs. In contrast, tumors broadly repressed chemokines and innate immune mediators, yet upregulated prostate cancer-associated lncRNAs, indicating local immune quiescence coupled with non-coding regulatory programs. Recurrent tumors acquired epithelial–mesenchymal transition and metabolic remodeling, accompanied by relapse-associated lncRNA signatures, whereas long-term nonrecurrent tumors preserved epithelial and stress-response networks. High-dimensional cytometry confirmed discrete, cancer-enriched myeloid clusters expressing CD47, SIRPα, PD-L1, CD73, and Galectin-9. Network analysis highlighted inflammatory hubs (CXCL2, PTGS2) in PBMCs and loss of mechanotransduction modules in tumors. Structural modeling uncovered a three-way junction and 3′ triple helix in lncRNA. Collectively, these data suggest that circulating inflammatory rewiring is associated with checkpoint-rich suppressor expansion and tumor immune quiescence, outlining integrated myeloid- and RNA-directed strategies for cancer research.
Source link
Pedro Reyes Martinez www.mdpi.com
