Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Nathan E Reticker-Flynn; Weiruo Zhang; Julia A Belk; Pamela A Basto; Nichole K Escalante; Genay O W Pilarowski; Alborz Bejnood; Maria M Martins; Justin A Kenkel; Ian L Linde; Sreya Bagchi; Robert Yuan; Serena Chang; Matthew H Spitzer; Yaron Carmi; Jiahan Cheng; Lorna L Tolentino; Okmi Choi; Nancy Wu; Christina S Kong; Andrew J Gentles; John B Sunwoo; Ansuman T Satpathy; Sylvia K Plevritis; Edgar G Engleman

doi:10.1016/j.cell.2022.04.019

Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Cell. 2022 May 26;185(11):1924-1942.e23. doi: 10.1016/j.cell.2022.04.019. Epub 2022 May 6.

Authors

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

Affiliations

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.

Keywords: ISGs; MHC-I; NK cells; PD-L1; Tregs; interferon; lymph nodes; metastasis; regulatory T cells; tolerance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Immune Tolerance
Immunotherapy
Lymph Nodes*
Lymphatic Metastasis / pathology
Melanoma* / pathology
Mice

Abstract

Publication types

MeSH terms

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