Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Nathan E. Reticker-Flynn, Weiruo Zhang, Julia A. Belk, Pamela A. Basto, Nichole K. Escalante, Genay O.W. Pilarowski, Alborz Bejnood, Maria M. Martins, Justin A. Kenkel, Ian L. Linde, Sreya Bagchi, Robert Yuan, Serena Chang, Matthew H. Spitzer, Yaron Carmi, Jiahan Cheng, Lorna L. Tolentino, Okmi Choi, Nancy Wu, Christina S. KongAndrew J. Gentles, John B. Sunwoo, Ansuman T. Satpathy, Sylvia K. Plevritis, Edgar G. Engleman

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


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 languageEnglish
Pages (from-to)1924-1942.e23
Issue number11
StatePublished - 26 May 2022
Externally publishedYes


  • ISGs
  • MHC-I
  • NK cells
  • PD-L1
  • Tregs
  • interferon
  • lymph nodes
  • metastasis
  • regulatory T cells
  • tolerance


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