CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8 + T Cells

The ability of CD8 T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8 T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39 CD8 T c...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 78; no. 1; pp. 115 - 128
Main Authors:	Canale, Fernando P, Ramello, María C, Núñez, Nicolás, Araujo Furlan, Cintia L, Bossio, Sabrina N, Gorosito Serrán, Melisa, Tosello Boari, Jimena, Del Castillo, Andrés, Ledesma, Marta, Sedlik, Christine, Piaggio, Eliane, Gruppi, Adriana, Acosta Rodríguez, Eva A, Montes, Carolina L
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research, Inc 01-01-2018
Subjects:	Adenosine Triphosphate - metabolism Animals Antigens, CD - metabolism Apyrase - metabolism ATP Breast cancer Breast Neoplasms - immunology Breast Neoplasms - pathology CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell surface Cytokines - metabolism Exhaustion Female Humans Immunosuppression Interleukin 2 Interleukin 27 Interleukin 6 Lymph nodes Lymphatic Metastasis - immunology Lymphatic Metastasis - pathology Lymphatic system Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Male Melanoma Melanoma - immunology Melanoma - pathology Metastases Mice, Inbred BALB C Mice, Knockout Nucleotidase Organs Peripheral blood Phenotypes Recovery of function T cell receptors Tumor Microenvironment - immunology Tumor necrosis factor Tumors Xenograft Model Antitumor Assays γ-Interferon
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Summary:	The ability of CD8 T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8 T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39 CD8 T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8 T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39 CD8 T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39 CD8 T cells inhibited IFNγ production by responder CD8 T cells. In specimens from breast cancer and melanoma patients, CD39 CD8 T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8 T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8 T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8 T cells, with implications for defining a biomarker of T-cell dysfunction and a target for immunotherapeutic intervention. The tumor microenvironment elicits a subset of functionally exhausted CD8 T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-16-2684