Cell. 2022 May 26;185(11):1924-1942.e23. doi: 10.1016/j.cell.2022.04.019. | PubMed

Nathan E Reticker-Flynn¹, Weiruo Zhang², Julia A Belk³, Pamela A Basto⁴, Nichole K Escalante³, Genay O W Pilarowski³, Alborz Bejnood², Maria M Martins³, Justin A Kenkel³, Ian L Linde³, Sreya Bagchi³, Robert Yuan³, Serena Chang⁵, Matthew H Spitzer⁶, Yaron Carmi⁷, Jiahan Cheng³, Lorna L Tolentino³, Okmi Choi³, Nancy Wu³, Christina S Kong⁸, Andrew J Gentles⁹, John B Sunwoo¹⁰, Ansuman T Satpathy¹¹, Sylvia K Plevritis¹², Edgar G Engleman¹³

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. 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.
6. Department of Microbiology and Immunology and Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA, USA.
7. Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
8. Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA.
9. Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Palo Alto, CA 94305, USA.
10. Department of Otolaryngology-Head & Neck Surgery, Stanford University, Palo Alto, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA.
11. 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.
12. Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Radiology, Stanford University, Palo Alto, CA 94305, USA.
13. Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA. Electronic address: edgareng@stanford.edu.

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.

Presented By Nathan E Reticker-Flynn | ORCID iD