A systemic neuroendocrine immune axis in breast cancer revealed by MMD regularized cross tissue latent alignment across four independent cohorts

Understanding systemic determinants of breast tumor immunity requires bridging transcriptomically distinct tissue compartments that cannot be sampled simultaneously in a single patient. We developed an MMD-regularized Domain Adaptation Autoencoder (DAA) to align unpaired RNA-seq profiles from GTEx neuroendocrine tissues ( n = 189 ) and TCGA-BRCA tumors ( n = 1391 ) within a shared 128-dimensional latent space, enabling the first cross-tissue transcriptomic interrogation of the neuroendocrine–breast tumor immune interface. The dominant cross-tissue axis was identified by Pearson correlation and rigorously validated by permutation testing ( n = 1000 iterations), then independently assessed in METABRIC microarray ( n = 1980 ) and SCAN-B RNA-seq ( n = 3273 ) cohorts via a strict gene-intersection protocol that eliminated zero-padding artefacts. The DAA achieved stable cross-domain alignment (mixing score = 26.58 % ), and Latent Dimension 31 emerged as a significant systemic immune-inflammatory axis ( p = 0.001 ; aggregate correlation 13.9 × above the permutation null), driven by T-cell receptor variable chains, immunoglobulin genes, and the tolerogenic phospholipase PLA2G2D . METABRIC validation recovered a mechanistically concordant acute-phase secretory signature ( LBP , SAA1 , PLA2G2A ), while SCAN-B confirmed PLA2G2D and CCL18 on a unified cross-platform latent axis. The latent score significantly stratified overall survival ( p = 0.0036 ) and relapse-free survival ( p = 0.0084 ), and precisely reproduced the established breast cancer immune topology across all six molecular subtypes (Kruskal–Wallis H = 139.4 , p < 0.0001 ). External validation in the independent neoadjuvant GEO cohort GSE25066 ( n = 508 ; Affymetrix GPL96) via a Strict Intersection Protocol (604-gene intersection, zero-padding eliminated) confirmed axis recovery (Latent Dimension 115; PLA2G2D | r | = 0.266 ), significant distant relapse-free survival stratification (log-rank p = 0.022 ), and non-significant pathological complete response to chemotherapy ( p = 0.241 ), establishing the axis as a prognostic but not predictive biomarker. Functional annotation in GSE25066 revealed significant correlation with all 12 curated immune cell signatures (Spearman ρ = 0.10 – 0.42 ; all p adj < 0.05 ), and GSEA pre-ranked analysis across 13,236 genes identified 34 significantly enriched Hallmark pathways (FDR < 0.25), led by Interferon Gamma Response (NES = 2.90 ) and opposed by Estrogen Response Early (NES = − 2.71 ). These findings, validated across 7152 patients in four independent cohorts, provide a computational transcriptomic framework linking systemic neuroendocrine regulation to breast tumor immunobiology and nominate PLA2G2D , SAA1 , and LBP as candidate circulating biomarkers warranting prospective proteomic validation.