Reticker-Flynn NE, Zhang W, Belk JA, Basto PA, Escalante NK, Pilarowski GOW, Bejnood A, Martins MM, Kenkel JA, Linde IL, Bagchi S, Yuan R, Chang S, Spitzer MH, Carmi Y, Cheng J, Tolentino LL, Choi O, Wu N, Kong CS, Gentles AJ, Sunwoo JB, Satpathy AT, Plevritis SK, Engleman EG.
Cell, 26 May 2022

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.