Abstract
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, padj<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.