Abstract LB324: STING protein expression is increased in intermediate luminal cells in proliferative inflammatory atrophy of the prostate (PIA) and is absent in the majority of primary prostatic adenocarcinomas
Authors: Steele Thomas M. , Meeker Alan K. , Graham Mindy K. , Wang Rulin , Gomes-Alexandre Carolina , Nelson William G. , Pereiria Fernanda Caramella , Kachhap Sushant , Yegnasubramanian Srinivasan , De Marzo Angelo Michael 
Published: April 2024

Abstract
Unresolved chronic inflammation has been postulated to drive prostate cancer development. We have proposed that proliferative inflammatory atrophy (PIA) can lead to the development of preneoplastic high grade prostatic intraepithelial neoplasia (PIN) lesions and/or directly to adenocarcinoma at times. Additionally, some PIA cells harbor molecular alterations seen in PIN and invasive carcinoma lesions, with a low frequency of PIA cells showing MYC over-expression, partial promoter hypermethylation and silencing of GSTP1, and formation of ETS gene fusions. PIA appears to result from inflammatory injury and regeneration in which proliferative and atrophic epithelial cells have an intermediate cell phenotype with both luminal and basal cell features, including basal cell markers, keratin 5 and BCL2, as well as varying levels of prostate luminal enriched genes such as androgen receptor, PSA and NKX3.1. Also, a number of gene products that are apparently stress induced, which are not expressed in normal prostate are induced in at least a subset of intermediate luminal cells in PIA, including GSTA1, PTGS2, LTF and PIGR (PMIDs:17384581, 37550827). Stimulator of interferon genes (STING), encoded by TMEM173, is a multipass transmembrane ER associated protein, and is a critical hub for innate responses directed against numerous bacterial, viral and parasitic pathogens, and is important for the induction and maintenance of adaptive immunity in a number of situations. Here, we examined STING expression by IHC, using a genetically validated assay, and show that the majority of atrophic prostatic luminal epithelial cells in all PIA lesions (N=20) consistently express high levels of STING, which is present in normal prostatic basal epithelial cells yet absent in normal-appearing prostatic luminal cells. In primary prostatic adenocarcinomas (&gt; 260 tumors), STING protein was either completely negative , or extremely low in ~ 95% of cases. That STING in PIA is activate is supported by single cell RNA sequencing (scRNAseq) data from human prostatectomy tissues that show cells with the phenotype of intermediate luminal cells, indicative of PIA, express a number of interferon response genes that are not expressed in normal luminal cells (PMID 37905029). To our knowledge this is the first systematic report of STING protein staining in human prostate cancer and benign tissues. We postulate that upregulation of STING in human intermediate cells in PIA represents an inflammatory response that can drive interferon stimulated gene expression and inflammation in PIA. This innate immune response is absent, potentially by gene silencing, in prostatic adenocarcinoma, which may help neoplastic cells evade the immune response and could help contribute to the long standing finding that most prostate cancers are immunologically cold.
Citation Format: Thomas M. Steele, Alan K. Meeker, Mindy K. Graham, Rulin Wang, Carolina Gomes-Alexandre, William G. Nelson, Fernanda Caramella Pereiria, Sushant Kachhap, Srinivasan Yegnasubramanian, Angelo Michael De Marzo. STING protein expression is increased in intermediate luminal cells in proliferative inflammatory atrophy of the prostate (PIA) and is absent in the majority of primary prostatic adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB324.