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IRF8 Governs Tumor-Associated Macrophage Control of T Cell Exhaustion

69 Pages Posted: 27 Mar 2020 Publication Status: Review Complete

See all articles by Briana Nixon

Briana Nixon

Memorial Sloan Kettering Cancer Center - Immunology Program

Fengshen Kuo

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Ming Liu

Memorial Sloan Kettering Cancer Center - Immunology Program

Kristelle Capistrano

Memorial Sloan Kettering Cancer Center - Immunology Program

Mytrang Do

Memorial Sloan Kettering Cancer Center - Immunology Program

Ruth Franklin

Memorial Sloan Kettering Cancer Center - Immunology Program

Xiaodi Wu

Washington University in St. Louis - Department of Pathology and Immunology

Emily Kansler

Memorial Sloan Kettering Cancer Center - Immunology Program

Raghvendra Srivastava

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Tanaya Purohit

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Alejandro Sanchez

Memorial Sloan Kettering Cancer Center - Urology Service

Lynda Vuong

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Chirag Krishna

Memorial Sloan Kettering Cancer Center - Computational and Systems Biology Program

Herbert Morse III

Memorial Sloan Kettering Cancer Center - Urology Service

James Hsieh

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Timothy A. Chan

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Kenneth M. Murphy

Washington University in St. Louis - Department of Pathology and Immunology

James J. Moon

Harvard Medical School - Center for Immunology and Inflammatory Diseases

Ari Hakimi

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

Ming O. Li

Memorial Sloan Kettering Cancer Center - Immunology Program

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Abstract

Tumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion.  How T cell exhaustion is elicited in the tumor remains poorly understood. Here we show that tumor-associated macrophages (TAMs) present cancer cell antigen and induce CTL exhaustion through a gene expression program dependent on the transcription factor interferon regulatory factor-8 (IRF8). In a transgenic model of murine breast cancer, CTL priming was supported by IRF8-dependent dendritic cells; yet, CTL exhaustion required TAM expression of IRF8, and its ablation suppressed tumor growth.  An analysis of the highly immune-infiltrated human renal cell carcinomatumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature.  The IRF8 signature co-segregated with T cell exhaustion markers and was negatively associated with long-term patient survival.  Thus, CTL exhaustion is promoted by TAMs via IRF8, and this crosstalk may be disrupted in TAM-targeted therapies.

Keywords: Tumor-associated macrophage, antigen presentation, cytotoxic T lymphocyte, cancer

Suggested Citation

Nixon, Briana and Kuo, Fengshen and Liu, Ming and Capistrano, Kristelle and Do, Mytrang and Franklin, Ruth and Wu, Xiaodi and Kansler, Emily and Srivastava, Raghvendra and Purohit, Tanaya and Sanchez, Alejandro and Vuong, Lynda and Krishna, Chirag and Morse III, Herbert and Hsieh, James and Chan, Timothy A. and Murphy, Kenneth M. and Moon, James J. and Hakimi, Ari and Li, Ming O., IRF8 Governs Tumor-Associated Macrophage Control of T Cell Exhaustion. Available at SSRN: https://ssrn.com/abstract=3554068 or http://dx.doi.org/10.2139/ssrn.3554068
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Briana Nixon

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Fengshen Kuo

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Ming Liu

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Kristelle Capistrano

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Mytrang Do

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Ruth Franklin

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Xiaodi Wu

Washington University in St. Louis - Department of Pathology and Immunology

One Brookings Drive
Campus Box 1208
Saint Louis, MO 63130-4899
United States

Emily Kansler

Memorial Sloan Kettering Cancer Center - Immunology Program

NYC, NY
United States

Raghvendra Srivastava

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Tanaya Purohit

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Alejandro Sanchez

Memorial Sloan Kettering Cancer Center - Urology Service

United States

Lynda Vuong

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Chirag Krishna

Memorial Sloan Kettering Cancer Center - Computational and Systems Biology Program

United States

Herbert Morse III

Memorial Sloan Kettering Cancer Center - Urology Service

United States

James Hsieh

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Timothy A. Chan

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Kenneth M. Murphy

Washington University in St. Louis - Department of Pathology and Immunology

One Brookings Drive
Campus Box 1208
Saint Louis, MO 63130-4899
United States

James J. Moon

Harvard Medical School - Center for Immunology and Inflammatory Diseases

250 Longwood Avenue
Boston, MA 02115
United States

Ari Hakimi

Memorial Sloan Kettering Cancer Center - Immunogenomics & Precision Oncology Platform (IPOP)

New York, NY 10065
United States

Ming O. Li (Contact Author)

Memorial Sloan Kettering Cancer Center - Immunology Program ( email )

NYC, NY
United States

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