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.
Original language | English |
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Pages (from-to) | 1924-1942.e23 |
Journal | Cell |
Volume | 185 |
Issue number | 11 |
DOIs | |
State | Published - 26 May 2022 |
Externally published | Yes |
Keywords
- ISGs
- MHC-I
- NK cells
- PD-L1
- Tregs
- interferon
- lymph nodes
- metastasis
- regulatory T cells
- tolerance
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology