Di Pilato et al. showed that CXCR6 controls growth of immunogenic tumors by regulating intratumoral accumulation of TCF-1- PD-1+ TIM-3- CD8+ effector-like antitumor CTLs, which emerge from TCF-1+ TIM-3+ stem-like CD8+ T cells. Intravital microscopy detected CXCR6+ TCF-1- CTLs in perivascular niches of tumor stroma adjacent to CCR7+ DC3, a recently identified DC subset that expresses CXCL16, the CXCR6 ligand. DC3 trans-presented IL-15 to promote intratumoral survival and expansion of effector-like CTLs. Of all the chemokine receptor genes, CXCR6 expression best predicted prolonged patient survival from multiple types of immunogenic solid cancers.
Contributed by Paula Hochman
ABSTRACT: Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7(+) dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7(+) DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.
Author Info: (1) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Immunology,
Author Info: (1) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: mdi@mdanderson.org. (2) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universitt Mnchen, Munich, Germany. (3) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. (4) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. (5) Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA. (6) Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universitt Mnchen, Munich, Germany. (7) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (8) Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA. (9) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA. (10) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. (11) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. (12) Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universitt Mnchen, Munich, Germany. (13) Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard School of Public Health, Boston, MA 21205, USA. (14) Department of Molecular Microbiology and Immunology and Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. (15) Department of Molecular Microbiology and Immunology and Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. (16) Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA. (17) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. (18) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (19) Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universitt Mnchen, Munich, Germany; German Center for Translational Cancer Research (DKTK), partner site, Munich, Germany. (20) Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA; Department of Pathology and Immunology, University of Geneva, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland. (21) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02115, USA. Electronic address: tmempel@mgh.harvard.edu.
