Pan-cancer computational analysis of adaptive immune and vascular changes in primary versus metastatic tumors.

Abstract

3124 Background: Metastasis drives cancer mortality, yet tumor microenvironment (TME) evolution during systemic spread remains poorly understood. Current paradigms often assume uniform immunosuppression at metastatic sites or seek a universal pro-metastatic signature. We investigated whether a conserved immune signature exists across metastatic sites or if remodeling follows tissue-specific trajectories that could inform precision therapeutic strategies. Methods: We performed computational meta-analysis from TCGA using xCell enrichment scores across >20,000 transcriptomic samples from primary tumors and distant metastases in five solid tumor types: Lung (n=1,622), Breast (n=1,543), Kidney (n=1,541), Brain (n=1,243), and Thyroid (n=1,016). Mann-Whitney U testing with Bonferroni correction identified cell populations with differential enrichment (padj<0.05). Cohorts were balanced for age, gender, and race (all p>0.05). Results: We identified two convergent metastatic trajectories with opposite directional changes in a four-cell plasticity module: B-cells, class-switched memory B-cells, CD4+ effector memory T-cells, and platelets. The Immune-Vascular Acquisition Trajectory (Breast, Brain, Thyroid) showed metastatic enrichment of all four cell types (Mean Difference [Primary-Metastatic]: -0.62; padj<0.001). The Immune-Vascular Depletion Trajectory (Lung, Kidney) showed significant depletion of all four populations at metastatic sites (Mean Difference [Primary-Metastatic]: +0.74; padj<0.001). Platelet dynamics consistently mirrored adaptive immune trajectories across all cancer types. Conclusions: These findings challenge two prevailing assumptions: uniform immunosuppression at metastatic sites and a single universal pro-metastatic immune signature. Instead, metastatic immune remodeling follows organ-specific convergent trajectories driven by adaptive and vascular plasticity. The identification of shared trajectories among biologically distinct cancers suggests that metastatic site microenvironment dictates TME evolution. The de novo acquisition of immune signatures in brain metastases challenges the "immunologically cold metastasis" paradigm, while depletion in naturally immunogenic tumors (Lung, Kidney) indicates TME "cooling" for immune evasion. The invariant coupling of platelet and adaptive immune dynamics highlights vascular remodeling as critical to metastatic niche establishment. These distinct trajectories may explain differential responses to immunotherapy and anti-angiogenic agents across metastatic sites, supporting the need for organ-specific therapeutic strategies. Future studies are needed to investigate whether primary tumors harbor early signatures of this module predictive of metastatic trajectory, enabling stratified surveillance and intervention.