Project description:The management of intermediate-risk early prostate cancer (PCa) is challenging due to the difficulty in distinguishing indolent from aggressive tumors. This study explores the impact of genomic alterations on the tumor and its microenvironment (TME). We performed multi-omic profiling in a cohort of 53 localized PCa using targeted sequencing, transcriptional and proteomic spatial profiling. Somatic mutations and copy number alterations in RB1 (21%), PTEN (18%), and TP53 (9%) were identified. Kaplan-Meier analysis revealed that alterations in the RB and Cell Cycle pathways, particularly aberrations in PTEN, TP53, or RB1, were associated with shorter biochemical recurrence-free survival (p < 0.001). Spatial proteomic analysis demonstrated a complex immune landscape in patients with mutations. The tumor compartment demonstrated higher expression of immune checkpoint markers, T-cell activation proteins, and proliferation markers; and a TME that is enriched with CD8+ T cells and antigen-presenting cells, but also with immunosuppressive M2 macrophages, suggesting adaptive immune resistance. Our analysis demonstrates that genomic alterations in PTEN, TP53, or RB1 are not only prognostic for poor outcomes but also actively shape a unique, immunologically active yet suppressed TME.
Project description:The management of intermediate-risk early prostate cancer (PCa) is challenging due to the difficulty in distinguishing indolent from aggressive tumors. This study explores the impact of genomic alterations on the tumor and its microenvironment (TME). We performed multi-omic profiling in a cohort of 53 localized PCa using targeted sequencing, transcriptional and proteomic spatial profiling. Somatic mutations and copy number alterations in RB1 (21%), PTEN (18%), and TP53 (9%) were identified. Kaplan-Meier analysis revealed that alterations in the RB and Cell Cycle pathways, particularly aberrations in PTEN, TP53, or RB1, were associated with shorter biochemical recurrence-free survival (p < 0.001). Spatial proteomic analysis demonstrated a complex immune landscape in patients with mutations. The tumor compartment demonstrated higher expression of immune checkpoint markers, T-cell activation proteins, and proliferation markers; and a TME that is enriched with CD8+ T cells and antigen-presenting cells, but also with immunosuppressive M2 macrophages, suggesting adaptive immune resistance. Our analysis demonstrates that genomic alterations in PTEN, TP53, or RB1 are not only prognostic for poor outcomes but also actively shape a unique, immunologically active yet suppressed TME.
