Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy

Chen Wang¹, Qun Zeng², Zeynep Melis Gül², Sisi Wang³, Robert Pick², Phil Cheng⁴, Ruben Bill⁵, Yan Wu⁶, Stefan Naulaerts⁷, Coline Barnoud², Pei-Chun Hsueh⁸, Sofie Hedlund Moller⁸, Mara Cenerenti², Mengzhu Sun², Ziyang Su², Stéphane Jemelin², Volodymyr Petrenko⁹, Charna Dibner⁹, Stéphanie Hugues¹⁰, Camilla Jandus¹¹, Zhongwu Li⁶, Olivier Michielin¹², Ping-Chih Ho⁸, Abhishek D Garg⁷, Federico Simonetta¹³, Mikaël J Pittet¹⁴, Christoph Scheiermann¹⁵

Affiliations

¹ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. Electronic address: chen.wang.1@unige.ch.
² Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
³ Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland.
⁴ Department of Oncology and Precision Oncology Service, Geneva University Hospitals, University of Geneva, Geneva 1211, Switzerland.
⁵ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; AGORA Cancer Research Center, Lausanne 1011, Switzerland; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
⁶ Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
⁷ Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
⁸ Department of Fundamental Oncology, University of Lausanne, Lausanne 1066, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland.
⁹ Division of Thoracic and Endocrine Surgery, Department of Surgery, Geneva University Hospitals, Geneva 1205, Switzerland; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), Geneva 1211, Switzerland.
¹⁰ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹¹ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹² Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Department of Oncology and Precision Oncology Service, Geneva University Hospitals, University of Geneva, Geneva 1211, Switzerland.
¹³ Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Division of Hematology, Department of Oncology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
¹⁴ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; AGORA Cancer Research Center, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹⁵ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), Geneva 1211, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland; Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) Munich, Planegg-Martinsried 82152, Germany. Electronic address: christoph.scheiermann@unige.ch.

PMID: 38723627
DOI: 10.1016/j.cell.2024.04.015

Free article

Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy

Chen Wang et al. Cell. 2024.

Free article

. 2024 May 23;187(11):2690-2702.e17.

doi: 10.1016/j.cell.2024.04.015. Epub 2024 May 8.

Authors

Affiliations

¹ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. Electronic address: chen.wang.1@unige.ch.
² Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
³ Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland.
⁴ Department of Oncology and Precision Oncology Service, Geneva University Hospitals, University of Geneva, Geneva 1211, Switzerland.
⁵ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; AGORA Cancer Research Center, Lausanne 1011, Switzerland; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
⁶ Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
⁷ Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
⁸ Department of Fundamental Oncology, University of Lausanne, Lausanne 1066, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland.
⁹ Division of Thoracic and Endocrine Surgery, Department of Surgery, Geneva University Hospitals, Geneva 1205, Switzerland; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), Geneva 1211, Switzerland.
¹⁰ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹¹ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹² Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Department of Oncology and Precision Oncology Service, Geneva University Hospitals, University of Geneva, Geneva 1211, Switzerland.
¹³ Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Division of Hematology, Department of Oncology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
¹⁴ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; AGORA Cancer Research Center, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, Lausanne 1005, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland.
¹⁵ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Translational Research Centre in Onco-Hematology (CRTOH), Geneva 1211, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), Geneva 1211, Switzerland; Geneva Centre for Inflammation Research (GCIR), Geneva 1211, Switzerland; Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) Munich, Planegg-Martinsried 82152, Germany. Electronic address: christoph.scheiermann@unige.ch.

PMID: 38723627
DOI: 10.1016/j.cell.2024.04.015

Abstract

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8⁺ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Keywords: BMAL1; CAR T therapy; PD-1; chronotherapy; circadian; immune checkpoint blockade; immunology; melanoma; tumor-infiltrating leukocyte.

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Conflict of interest statement

Declaration of interests C.S. has been a consultant for Bayer and received speaker fees from Abbvie. M.J.P. has been a consultant for AstraZeneca, Debiopharm, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, MaxiVax, Merck, Molecular Partners, Third Rock Ventures, and Tidal. F.S. received consulting fees from BMS/Celgene, Incyte, Kite/Gilead, speaker fees from Kite/Gilead, Incyte, travel support from Kite/Gilead, Novartis, AstraZeneca, Neovii, Janssen, and research funding from Kite/Gilead, Novartis, and BMS/Celgene. A.D.G. received consulting/advisory/lecture honoraria or research funding from Boehringer Ingelheim, SOTIO, Miltenyi Biotec, Novigenix, and IsoPlexis. R.B. received speaker fees from Janssen and is a mentee of the ENDEAVOUR-Breast program of Daichii Sankyo. All these relationships are unrelated to this study.

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Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy

Affiliations

Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Molecular Biology Databases

Research Materials