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Immune Mechanisms Orchestrate Tertiary Lymphoid Structures in Tumors Via Cancer-Associated Fibroblasts

64 Pages Posted: 28 Apr 2020 Publication Status: Review Complete

See all articles by Anthony Rodriguez

Anthony Rodriguez

University of Virginia - Beirne B Carter Center for Immunology Research

J. David Peske

University of Virginia - Beirne B Carter Center for Immunology Research

Amber N. Woods

University of Virginia - Beirne B Carter Center for Immunology Research

Katie M. Leick

University of Virginia - Beirne B Carter Center for Immunology Research

Ileana S. Mauldin

University of Virginia - Beirne B Carter Center for Immunology Research

Samuel J. Young

University of Virginia - Beirne B Carter Center for Immunology Research

Robin S. Lindsay

University of Virginia - Beirne B Carter Center for Immunology Research

Marit M. Melssen

University of Virginia - Beirne B Carter Center for Immunology Research

Salwador Cyranowski

University of Virginia - Beirne B Carter Center for Immunology Research

Geoffrey Parriott

University of Virginia - Beirne B Carter Center for Immunology Research

Max O. Meneveau

University of Virginia - Department of Surgery

Mark R. Conaway

University of Virginia

Yang-Xin Fu

University of Texas at Dallas

Craig L. Slingluff Jr

University of Virginia - Beirne B Carter Center for Immunology Research

Victor H. Engelhard

University of Virginia - Beirne B Carter Center for Immunology Research

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Abstract

Tertiary lymphoid structures (TLS) are lymphoid aggregates resembling secondary lymphoid organs found at sites of inflammation. TLS have been identified in tumors (TA-TLS), where they are associated with enhanced patient survival, but the mechanisms underlying their formation are unknown. We show here that TA-TLS development in murine melanomas is orchestrated by fibroblasts with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. Fibroblast organization into reticular networks is initiated by CD8 T-cells, but full TA-TLS development depends on CXCL13-mediated recruitment of B-cells that express lymphotoxin-α12. Some of these elements were also overrepresented in TA-TLS of human tumors. Immune checkpoint blockade induced more and larger TA-TLS that were more often organized with discrete T- and B-cell zones. This work provides a platform for manipulating TA-TLS as a cancer immunotherapy strategy.

Keywords: B16, CD8 T-cells, B-cells, Tumor necrosis factor receptor, Lymphotoxin-beta receptor, Lymphoid tissue organizer cells, Lymphoid tissue inducer cell, Checkpoint blockade immunotherapy

Suggested Citation

Rodriguez, Anthony and Peske, J. David and Woods, Amber N. and Leick, Katie M. and Mauldin, Ileana S. and Young, Samuel J. and Lindsay, Robin S. and Melssen, Marit M. and Cyranowski, Salwador and Parriott, Geoffrey and Meneveau, Max O. and Conaway, Mark R. and Fu, Yang-Xin and Slingluff Jr, Craig L. and Engelhard, Victor H., Immune Mechanisms Orchestrate Tertiary Lymphoid Structures in Tumors Via Cancer-Associated Fibroblasts. Available at SSRN: https://ssrn.com/abstract=3575119 or http://dx.doi.org/10.2139/ssrn.3575119
This version of the paper has not been formally peer reviewed.

Anthony Rodriguez

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

J. David Peske

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Amber N. Woods

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Katie M. Leick

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Ileana S. Mauldin

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Samuel J. Young

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Robin S. Lindsay

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Marit M. Melssen

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Salwador Cyranowski

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Geoffrey Parriott

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Max O. Meneveau

University of Virginia - Department of Surgery ( email )

United States

Mark R. Conaway

University of Virginia ( email )

1400 University Ave
Charlottesville, VA 22903
United States

Yang-Xin Fu

University of Texas at Dallas ( email )

2601 North Floyd Road
Richardson, TX 75083
United States

Craig L. Slingluff Jr

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

Victor H. Engelhard (Contact Author)

University of Virginia - Beirne B Carter Center for Immunology Research ( email )

United States

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