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1.
J Exp Med ; 220(9)2023 09 04.
Article in English | MEDLINE | ID: mdl-37341991

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.


Subject(s)
Breast Neoplasms , Humans , Animals , Mice , Female , Breast Neoplasms/pathology , Cell Plasticity , Lymph Nodes , T-Lymphocytes, Regulatory , Lymphatic Metastasis/pathology , Immune Tolerance , Melanoma, Cutaneous Malignant
2.
Cell Stem Cell ; 28(11): 1922-1935.e5, 2021 11 04.
Article in English | MEDLINE | ID: mdl-34529935

ABSTRACT

Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNγ) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II-) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.


Subject(s)
Histocompatibility Antigens Class II , Intestines , Carcinogenesis , Diet, High-Fat , Epithelial Cells , Humans
3.
Adv Exp Med Biol ; 1244: 37-50, 2020.
Article in English | MEDLINE | ID: mdl-32301009

ABSTRACT

Diagnostic procedures play critical roles in cancer immunotherapy. In this chapter, we briefly discuss three major diagnostic procedures widely used in immunotherapy: immunohistochemistry, next-generation sequencing, and flow cytometry. We also describe the uses of other diagnostic procedures and preclinical animal models in cancer immunotherapy translational research.


Subject(s)
Flow Cytometry , High-Throughput Nucleotide Sequencing , Immunohistochemistry , Immunotherapy , Neoplasms/diagnosis , Neoplasms/therapy , Animals , Humans , Neoplasms/immunology
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