Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.

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.

Journal for immunotherapy of cancer. 2022 Jun [Epub]

Anna Sofia Trigos, Anupama Pasam, Patricia Banks, Roslyn Wallace, Christina Guo, Simon Keam, Heather Thorne, kConFab , Catherine Mitchell, Stephen Lade, David Clouston, Alexander Hakansson, Yang Liu, Benjamin Blyth, Declan Murphy, Nathan Lawrentschuk, Damien Bolton, Daniel Moon, Phil Darcy, Ygal Haupt, Scott G Williams, Elena Castro, David Olmos, David Goode, Paul Neeson, Shahneen Sandhu

Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Institute of Cancer Research Sutton, Sutton, Surrey, UK., Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., TissuPath, Melbourne, Victoria, Australia., Veracyte Inc, South San Francisco, California, USA., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Austin Hospital, Heidelberg, Victoria, Australia., Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Instituto de Investigacion Biomedica de Malaga, Malaga, Spain., Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia .

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