Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance

Lymph-node (LN) colonization in cancer is linked to poor prognosis and often precedes distant metastases. Evidence suggests that LN-colonization induces systemic immunosuppression facilitating distant metastasis. We investigated LN-mediated immunosuppression in head-and-neck cancer patients using spatial proteomics, spatial transcriptomics, and an in-vivo model of melanoma LN-metastasis. Both primary tumors and paired LNs of nodal-positive patients exhibit enhanced interferon-signaling and an enrichment of immunosuppressive myeloid cells and cancer-associated fibroblasts (CAFs). The spatial intersection of these myeloid-CAF-enriched niches with perifollicular T-cell-zones and LN-follicles are linked to enhanced T-cell dysfunction and Treg activation therein, thereby driving architectural LN remodeling. These immune suppressive changes extend to adjacent non-tumor-involved LN regions and nearby tumor-free LNs, but were not detected in LNs of non-cancer patients, reflecting a systemic effect that compromises anti-tumor immunity beyond the tumor-infested LN. Hence, our findings establish LN colonization as an active driver of systemic immunosuppression, facilitating metastatic progression.

The files provided include:
(1) Single cell data table of the pre-processed and normalized CODEX imaging data from the HNSCC discovery cohort (U54_CODEX_HNSCC_full_df_070125)
(2) Single cell data table of the pre-processed and normalized orthogonally collected spatial transcriptomics data from a subset of the HNSCC discovery cohort (U54_spatial_transcriptomics_070125)
(3) Single cell data table of the pre-processed and normalized CODEX imaging from the HNSCC validation cohort and Healthy LN tissue atlas (U54_HNSCC_Normal_LN_TMA_Validation_170825)
(4) Associated clinical metadata files for both the HNSCC discovery, HNSCC validation and Normal LN TMA cohorts.
(5) Single cell data table of the pre-processed and normalized CODEX imaging dataset from our in-vivo melanoma model of LN-metastasis (Murine_data_metadata_concat_070125)