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Cancer Cell. 2019 Jun 10;35(6):885-900.e10. doi: 10.1016/j.ccell.2019.05.004.

Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors.

Author information

1
Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland.
2
Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
3
Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; University of Chicago, Knapp Center for Biomedical Discovery, Department of Hematology & Oncology, Chicago, IL 60637, USA.
4
Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Cell and Gene Therapy, OTAT/CBER/FDA, Silver Spring, MD 20993, USA.
5
Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
6
Russ College of Engineering and Technology, Ohio University, Athens, OH 45701, USA.
7
Department of Immunology and Gynecologic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
8
SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; International Microbiome Centre, University of Calgary, Calgary, AB, Canada.
9
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
10
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
11
Bristol-Myers Squibb, Princeton, NJ 08540, USA.
12
Laura and Isaac Perlmutter Cancer Center, New York University, 522 First Avenue, Room 1310 Smilow Building, New York, NY 10016, USA.
13
Department of Pathology, Brigham & Women's Hospital, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
14
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
15
Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland; 2nd Department of Pathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens 12464, Greece.
16
Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. Electronic address: george.coukos@chuv.ch.

Abstract

We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

KEYWORDS:

CCL5; CXCL10; CXCL9; IFN-γ; T cell trafficking in the tumor; TILs (tumor-infiltrating lymphocytes); checkpoint blockade; epigenetic silencing; immunoreactive tumors; inducible and constitutive chemokines

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