Colonization of the lymph node promotes distant organ metastasis through induction of immune tolerance.

  • Major Finding: Colonization of the lymph node promotes distant organ metastasis through induction of immune tolerance.

  • Concept: IFN signaling induces epigenetic changes increasing MHC-1 and PD-L1 expression and altering tumor immunity.

  • Impact: This work reveals a conserved mechanism of distant metastasis that can be targeted in patients with advanced disease.


Metastatic disease is typically preceded by lymph node (LN) involvement, which serves as a prognostic factor in many solid tumors. LNs serve as immune cell education sites that can contribute to potent antitumor immunity; however, the possible role for LNs in tumor dissemination and the mechanisms that underlie tumor immune escape in this location remain unknow. Reticker-Flynn and colleagues sought to address this through development and use of a syngeneic melanoma LN metastasis model to investigate the effects LN metastases may have on distant tissue colonization. LN metastasis was found to enhance the ability of tumors to colonize distant organs, and analysis of differential gene expression revealed an enrichment of genes related to immune response, specifically type I and II IFN responses, while those related to cell cycle were the most reduced. Additionally, parental and LN metastatic lines were epigenetically distinct, with LN metastases showing activity of IFN-stimulated response elements and other IFN-regulatory factor binding motifs suggesting that epigenetic reprogramming aids in driving the LN metastatic phenotype. Both Cd274 (which encodes PD-L1) and B2m gene expression, which are known IFN-inducible genes, were also upregulated in LN metastatic cell line generations leading to increased PD-L1 and major histocompatibility complex (MHC) class I molecules on the cell surface, with the more immediate upregulation of MHC class I molecules contributing to natural killer cell evasion and PD-L1 upregulation facilitating T-cell suppression. Furthermore, along with suppression of T-cell response, induction of regulatory T cells (Treg) was observed with LN metastases, with these Tregs being antigen specific and demonstrating the ability to promote distant metastasis. In summary, this study developed a model that revealed LN metastases play a large role in promotion of subsequent metastasis to distant tissues through induction of immune tolerance making distant tissues amenable to metastatic colonization. This suggests immune response repolarization in the LNs as a potential approach to enhance therapy response in patients with advanced disease.

Reticker-Flynn NE, Zhang W, Belk JA, Basto PA, Escalante NK, Pilarowki GOW, et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell 2022;185:1924–42.e23.

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