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

Lei et al. uncover that a subpopulation of breast cancer cells in the lymph node is marked by MHC-II expression in the absence of costimulatory molecules, which causes the expansion of immunosuppressive regulatory T cells. 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.

Automated summary

Lei et al. uncover that a subpopulation of breast cancer cells in the lymph node express MHC-II without costimulatory molecules, resulting in the expansion of immunosuppressive regulatory T cells. Tumor-draining lymph nodes play a crucial role in generating tumor antigen-specific T cells and effective anticancer immune responses. However, these lymph nodes are frequently the site of metastasis, leading to immune suppression and poorer outcomes.