Investigating the relationship between lymph node (LN) and distant metastases, Reticker-Flynn et al. developed a mouse model of LN metastasis by repeatedly inoculating B16 melanoma tumors, collecting LN-metastatic cells, and re-inoculating these cells. Mice with 6th-gen (versus parental) primary tumors had increased lung metastasis after i.v. injection of the parental line. Across generations, transcriptomic and epigenetic changes in IFN-related genes and increases in MHC-I/B2M and PD-L1 expression conferred resistance to NK and T cells. Tumor antigen-specific Tregs were expanded in metastatic LNs and supported lung colonization.
Contributed by Alex Najibi
ABSTRACT: For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: retickerflynn@stanford.edu. (2) Department of Biomedical Data Science, Stanford Unive
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: retickerflynn@stanford.edu. (2) Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA. (3) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (4) Division of Oncology, Department of Medicine, Stanford University, Palo Alto, CA 94305, USA. (5) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (6) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (7) Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA. (8) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (9) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (10) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (11) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (12) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (13) Institute for Immunity, Transplantation, and Infection Operations, Stanford University, Palo Alto, CA 94305, USA; Department of Otolaryngology-Head & Neck Surgery, Stanford University, Palo Alto, CA 94305, USA. (14) Department of Microbiology and Immunology and Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA, USA. (15) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (16) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (17) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (18) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (19) Department of Pathology, Stanford University, Stanford, CA 94305, USA. (20) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA. (21) Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Palo Alto, CA 94305, USA. (22) Department of Otolaryngology-Head & Neck Surgery, Stanford University, Palo Alto, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA. (23) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA. (24) Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Radiology, Stanford University, Palo Alto, CA 94305, USA. (25) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA. Electronic address: edgareng@stanford.edu.
