RT Journal Article
T1 Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
A1 Trigos, Anna Sofia
A1 Pasam, Anupama
A1 Banks, Patricia
A1 Wallace, Roslyn
A1 Guo, Christina
A1 Keam, Simon
A1 Thorne, Heather
A1 kConFab, 
A1 Mitchell, Catherine
A1 Lade, Stephen
A1 Clouston, David
A1 Hakansson, Alexander
A1 Liu, Yang
A1 Blyth, Benjamin
A1 Murphy, Declan
A1 Lawrentschuk, Nathan
A1 Bolton, Damien
A1 Moon, Daniel
A1 Darcy, Phil
A1 Haupt, Ygal
A1 Williams, Scott G
A1 Castro, Elena
A1 Olmos, David
A1 Goode, David
A1 Neeson, Paul
A1 Sandhu, Shahneen
K1 gene expression profiling
K1 genetic markers
K1 prostatic neoplasms
K1 tumor microenvironment
AB Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/20159
UL http://hdl.handle.net/10668/20159
LA en
DS RISalud
RD Apr 10, 2025