Abstract Sustained proinflammatory signaling drives cancer initiation in multiple organ systems. We have postulated that chronic inflammation may drive prostatic cancer development through proliferative inflammatory atrophy (PIA). PIA lesions appear to result from inflammatory injury and regeneration, and a small subset merges directly with high grade prostatic intraepithelial neoplasia (PIN) and at times early invasive adenocarcinoma. A subset of PIA luminal epithelial cells (Lu-PIA) display molecular features characteristic of PIN and invasive carcinoma lesions (PMIDs: 39198404, 34341114). We hypothesized that many Lu-PIA cells represent an intermediate cell state between basal and mature luminal cells (PMID 39198404) and show overlapping gene expression with “prostatic club-like cells” (PMID 39198404). We previously showed that STING was increased in Lu-PIA using iterative multiplex IHC (STING, NaKATPase, p63, Ki67, NKX3. 1, AR, GSTP1, CD45, CK903, CK8) on radical prostatectomies (AACR AM 2024: Abstract LB324). Here, additional samples were added and whole-slide scans were deconvoluted and fused, segmented into regions of interest (ROIs), phenotypically separated into basal and luminal cells, and analyzed separately across diagnostically normal (n=13), PIA (n=14), PIN (n=9), ATRMerge (n=6), urethra (n=3), and cancer regions (n=10). Fused images were analyzed using HALO (Indica Labs) with trained AI classifiers, allowing phenotypic separation of basal and luminal cells (65840 basal and 288644 luminal Cells Identified). Basal and Lu-PIA cells were strongly positive for STING, while normal, primary prostatic adenocarcinoma, and PIN luminal cells were negative. Using UMAP, Lu-PIA cells clustered in an unbiased manner separately from normal basal and luminal cells. Furthermore, RIG-I, a potential upstream regulator of STING expression, and MX1, an interferon-induced protein that is a potential downstream activation signal of STING activity, were elevated in PIA luminal cells and low in PIN and adenocarcinoma. We hypothesize that elevated STING, RIG-I, and MX1 protein levels in Lu-PIA cells represent an intrinsic innate immune response occurring in cells with an intermediate phenotype between basal and luminal cells. This leads to, or helps sustain, chronic inflammation and proinflammatory signaling leading to cell injury and regeneration, DNA damage and subsequent somatic alterations such as oncogenic mutations, and epigenetic alterations. In rare somatically altered cells, silencing of this intrinsic innate immune response may occur, allowing increases in MYC expression and activity, AR signaling, and evolution into neoplastic PIN and/or cancer cells. The dampened innate immune signaling in neoplastic luminal cells may contribute to the observation that prostate cancers are immunologically cold. Citation Format: Thomas M. Steele, Jessica Hicks, Qizhi Zheng, Alan K. Meeker, Mindy K. Graham, Abhishek Shetty, Rulin Wang, Carolina Gomes-Alexandre, Fernanda Caramella Pereira, William G. Nelson, Sushant Kachhap, Srinivasan Yegnasubramanian, Angelo M. De Marzo. Prostatic luminal epithelial cells in proliferative inflammatory atrophy display proinflammatory innate immune signaling activation that is absent in prostatic adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB079.
Steele et al. (Fri,) studied this question.