PhD student University of Cambridge Cambridge, England, United Kingdom
Disclosure(s):
Qiuchen Zhao, PhD: No financial relationships to disclose
Introduction/Rationale: Regional lymph node (LN) metastasis critically influences distant metastatic progression, anti-tumour immunity, and patient prognosis. While tumour-induced immune modulation in tumour-draining LNs (TDLNs) has been extensively studied using murine models, the systematic reconstruction of the immune system from primary tumours through TDLNs and subsequent lymph nodes in human cancer progression remains understudied.
Methods: Here, we utilised integrated multi-omics approaches, including imaging mass cytometry, single-cell RNA sequencing, Visium and Xenium spatial transcriptomics, and multi-colour immunofluorescence to systematically characterise immune cell dynamics across 147 paired primary tumours, sentinel TDLNs (S-TDLNs), and secondary axillary LNs (ALNs) obtained from 50 treatment-naïve triple-negative breast cancer patients with different progression statuses.
Results: We observe depletion of cDC2 and naïve T cells, with expansion of immunosuppressive MARCO⁺ macrophages associated with survival, as identified by a newly developed single-cell transformer model. Spatial analysis and a unified cell–cell interaction framework reveal disrupted immune communication and impaired dendritic cell–T cell priming circuits within metastatic LNs and matched tumours. In an independent neoadjuvant immunotherapy cohort (36 patients, 52 LNs), preservation of CD1c⁺ cDC2 predicts pathological complete response and prolonged event-free survival, positioning cDC2 as a biomarker and rational therapeutic target in TNBC.
Conclusion: Collectively, this systematic mapping of immune landscape alterations during human sequential LN metastasis provides essential insights for understanding cancer metastasis mechanisms and paves the way for innovative immunotherapeutic strategies.
