Lei and Pereira et al. performed a comprehensive analysis of breast cancer progression to lymph node metastases (LNM) at a single-cell resolution, and identified heterogeneous and spatially organized epithelial and mesenchymal phenotypes, with a subset of cancer cells expressing higher levels of the MHC-II gene in both human and mouse tumors. Invasion of MHC-II+ cancer cells into the lymph node expanded Tregs and induced immune tolerance. Overexpression of Ciita, an MHC-II transactivator, in 4T1 mouse tumor cells increased Treg expansion and LNM, whereas MHC-II knockout inhibited Treg expansion and LNM.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston,
Author Info: (1) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (2) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (3) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (4) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (5) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (6) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (7) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, MA, USA. ROR: https://ror.org/042nb2s44 (8) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (9) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (10) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (11) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology , Cambridge, MA, USA. ROR: https://ror.org/042nb2s44 (12) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (13) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (14) Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ROR: https://ror.org/02qz8b764 (15) Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ROR: https://ror.org/02qz8b764 (16) Department of Pathology and Laboratory Medicine, School of Medicine, Boston University, Boston, MA, USA. ROR: https://ror.org/05qwgg493 (17) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78 (18) Cold Spring Harbor Laboratory , Cold Spring Harbor, NY, USA. ROR: https://ror.org/02qz8b764 (19) Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ROR: https://ror.org/002pd6e78
