Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes

J Exp Med. 2023 Sep 4;220(9):e20221847. doi: 10.1084/jem.20221847. Epub 2023 Jun 21.


Tumor-draining lymph nodes (TDLNs) are important for tumor antigen-specific T cell generation and effective anticancer immune responses. However, TDLNs are often the primary site of metastasis, causing immune suppression and worse outcomes. Through cross-species single-cell RNA-Seq analysis, we identified features defining cancer cell heterogeneity, plasticity, and immune evasion during breast cancer progression and lymph node metastasis (LNM). A subset of cancer cells in the lymph nodes exhibited elevated MHC class II (MHC-II) gene expression in both mice and humans. MHC-II+ cancer cells lacked costimulatory molecule expression, leading to regulatory T cell (Treg) expansion and fewer CD4+ effector T cells in TDLNs. Genetic knockout of MHC-II reduced LNM and Treg expansion, while overexpression of the MHC-II transactivator, Ciita, worsened LNM and caused excessive Treg expansion. These findings demonstrate that cancer cell MHC-II expression promotes metastasis and immune evasion in TDLNs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Breast Neoplasms* / pathology
  • Cell Plasticity
  • Female
  • Humans
  • Immune Tolerance
  • Lymph Nodes
  • Lymphatic Metastasis / pathology
  • Melanoma, Cutaneous Malignant
  • Mice
  • T-Lymphocytes, Regulatory