Investigating the relationship between lymph node (LN) and distant metastases, Reticker-Flynn et al. developed a mouse model of LN metastasis by repeatedly inoculating B16 melanoma tumors, collecting LN-metastatic cells, and re-inoculating these cells. Mice with 6th-gen (versus parental) primary tumors had increased lung metastasis after i.v. injection of the parental line. Across generations, transcriptomic and epigenetic changes in IFN-related genes and increases in MHC-I/B2M and PD-L1 expression conferred resistance to NK and T cells. Tumor antigen-specific Tregs were expanded in metastatic LNs and supported lung colonization.
Contributed by Alex Najibi
ABSTRACT: For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.