Abstract

Downregulation of HLA class I (HLA-I) impairs immune recognition and surveillance in prostate cancer and may underlie the ineffectiveness of checkpoint blockade. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Here, we conducted a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Loss of HLA-I gene expression was associated with repressive chromatin states including DNA methylation, histone H3 tri-methylation at lysine 27, and reduced chromatin accessibility. Pharmacological DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition decreased DNA methylation and increased H3 lysine 27 acetylation and resulted in re-expression of HLA-I on the surface of tumor cells. Re-expression of HLA-I on LNCaP cells by DNMT and HDAC inhibition increased activation of co-cultured prostate specific membrane antigen (PSMA)27-38-specific CD8+ T-cells. HLA-I expression is epigenetically regulated by functionally reversible DNA methylation and chromatin modifications in human prostate cancer. Methylated HLA-I was detected in HLA-Ilow circulating tumor cells (CTCs), which may serve as a minimally invasive biomarker for identifying patients who would benefit from epigenetic targeted therapies.

Loss of HLA-I gene expression in prostate cancer is associated with repressive chromatin states, which can be reversed by pharmacological DNMT and HDAC inhibition leading to increased activation of co-cultured tumor-specific CD8+ T-cells.

Details

Title
Reversible epigenetic alterations regulate class I HLA loss in prostate cancer
Author
Rodems, Tamara S. 1   VIAFID ORCID Logo  ; Heninger, Erika 2 ; Stahlfeld, Charlotte N. 1 ; Gilsdorf, Cole S. 1 ; Carlson, Kristin N. 1 ; Kircher, Madison R. 1 ; Singh, Anupama 2 ; Krueger, Timothy E. G. 1 ; Beebe, David J. 3   VIAFID ORCID Logo  ; Jarrard, David F. 4 ; McNeel, Douglas G. 1   VIAFID ORCID Logo  ; Haffner, Michael C. 5 ; Lang, Joshua M. 2   VIAFID ORCID Logo 

 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Medicine, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Biomedical Engineering, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Pathology, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Urology, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
 Fred Hutchinson Cancer Research Center, Divisions of Human Biology and Clinical Research, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622); University of Washington, Department of Pathology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657); Johns Hopkins School of Medicine, Department of Pathology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2708890816
Copyright
© The Author(s) 2022. corrected publication 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.