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

Denarda Dangaj; Marine Bruand; Alizée J Grimm; Catherine Ronet; David Barras; Priyanka A Duttagupta; Evripidis Lanitis; Jaikumar Duraiswamy; Janos L Tanyi; Fabian Benencia; Jose Conejo-Garcia; Hena R Ramay; Kathleen T Montone; Daniel J Powell Jr; Phyllis A Gimotty; Andrea Facciabene; Donald G Jackson; Jeffrey S Weber; Scott J Rodig; Stephen F Hodi; Lana E Kandalaft; Melita Irving; Lin Zhang; Periklis Foukas; Sylvie Rusakiewicz; Mauro Delorenzi; George Coukos

doi:10.1016/j.ccell.2019.05.004

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

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

Authors

Denarda Dangaj¹, Marine Bruand¹, Alizée J Grimm¹, Catherine Ronet¹, David Barras², Priyanka A Duttagupta³, Evripidis Lanitis¹, Jaikumar Duraiswamy⁴, Janos L Tanyi⁵, Fabian Benencia⁶, Jose Conejo-Garcia⁷, Hena R Ramay⁸, Kathleen T Montone⁹, Daniel J Powell Jr⁵, Phyllis A Gimotty¹⁰, Andrea Facciabene⁵, Donald G Jackson¹¹, Jeffrey S Weber¹², Scott J Rodig¹³, Stephen F Hodi¹⁴, Lana E Kandalaft¹, Melita Irving¹, Lin Zhang⁵, Periklis Foukas¹⁵, Sylvie Rusakiewicz¹, Mauro Delorenzi², George Coukos¹⁶

Affiliations

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.

Publication types

Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism*
Cell Line, Tumor
Chemokine CCL5 / genetics
Chemokine CCL5 / immunology
Chemokine CCL5 / metabolism
Chemokine CXCL9 / genetics
Chemokine CXCL9 / immunology
Chemokine CXCL9 / metabolism
Chemotaxis, Leukocyte* / drug effects
Coculture Techniques
Cytokines / genetics
Cytokines / immunology
Cytokines / metabolism*
DNA Methylation
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / metabolism*
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic
Humans
Immunotherapy / methods
Interferon-gamma / genetics
Interferon-gamma / immunology
Interferon-gamma / metabolism
Lymphocyte Activation* / drug effects
Lymphocytes, Tumor-Infiltrating / drug effects
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism*
Macrophages / drug effects
Macrophages / immunology
Macrophages / metabolism*
Mice, Inbred C57BL
Ovarian Neoplasms / immunology
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / pathology
Ovarian Neoplasms / therapy
Paracrine Communication
Receptors, CXCR3 / genetics
Receptors, CXCR3 / immunology
Receptors, CXCR3 / metabolism
Signal Transduction

Substances

Antineoplastic Agents, Immunological
CCL5 protein, human
CXCL9 protein, human
CXCR3 protein, human
Chemokine CCL5
Chemokine CXCL9
Cytokines
IFNG protein, human
Receptors, CXCR3
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding