Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes.
Pin-Ji Lei, Ethel R Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J O'Melia, Hengbo Zhou, Sampurna Chatterjee, William W Ho, Jessica M Posada, Ashwin S Kumar, Satoru Morita, Lutz Menzel, Charlie Chung, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P Padera
Author Information
Pin-Ji Lei: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Ethel R Pereira: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Patrik Andersson: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Zohreh Amoozgar: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Jan Willem Van Wijnbergen: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Meghan J O'Melia: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Hengbo Zhou: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Sampurna Chatterjee: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
William W Ho: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Jessica M Posada: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Ashwin S Kumar: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Satoru Morita: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Lutz Menzel: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Charlie Chung: Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ORCID
Ilgin Ergin: Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ORCID
Dennis Jones: Department of Pathology and Laboratory Medicine, School of Medicine, Boston University, Boston, MA, USA. ORCID
Peigen Huang: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
Semir Beyaz: Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ORCID
Timothy P Padera: Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ORCID
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.
