Prostaglandin E2 curtails interleukin-2-dependent effector expansion from tumor-infiltrating stem-like CD8+ T cells to promote cancer immune escape
LACHER S. 1, DÖRR J. 6, ALMEIDA G. 3, HÖNNINGER J. 1,4, MEISER P. 1, BAYERL F. 1, PEDDE A. 1, HIRSCHBERGER A. 1, JAROSCH S. 4,10, GREGOR L. 2, BUSCH D. 5, BUCHHOLZ V. 5, KNOLLE P. 1, ZEHN D. 3, KOBOLD S. 2,7,8, BÖTTCHER J. 1
1 Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany; 2 Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU, Member of the German Center for Lung Research (DZL), Munich, Germany; 3 Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan (TUM), Freising, Germany; 4 Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM), Munich, Germany; 5 Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM), Munich, Germany; 6 Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU, Member of the German Center for Lung Research (DZL), Munich, Germany; 7 German Center for Translational Cancer Research (DKTK), partner site Munich , Munich, Germany; 8 Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Munich-Neuherberg, Germany; 9 Department of Medicine III, Klinikum der Universität München, LMU, Munich, Germany; 10 Present address: 15 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach An Der Riß, Germany
The ability of cancer-specific TCF1+ stem-like CD8+ T cells to promote protective anti-cancer immunity by expanding and differentiating into effector cells is compromised in many tumors. While current cancer immunotherapies can enhance the response of TCF1+ stem-like CD8+ T cells in some patients, other unidentified factors limit their anti-cancer capabilities.
In this study, we demonstrate that tumor-derived prostaglandin E2 (PGE2) restricts the proliferation and differentiation of tumor-infiltrating TCF1+CD8+ T cells, thereby facilitating tumor immune evasion. PGE2 secreted by tumors does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes, but it selectively inhibits the response of TCF1+CD8+ T cells within the tumor microenvironment. This inhibition is mediated through the EP2/EP4 receptor signaling in CD8+ T cells, which hinders the development of early and late effector T cell populations originating from tumor-infiltrating TCF1+CD8+ T cells. By abolishing the EP2/EP4 signaling in cancer-specific CD8+ T cells, their proliferation and effector differentiation can be restored at the tumor site, eliminating tumors in various mouse cancer models. Mechanistically, PGE2 suppresses the IL-2 signaling pathway, which inhibits intratumorally TCF1+CD8+ T cell responses.
This study uncovers a crucial mechanism that limits the IL-2 responsiveness of tumor-infiltrating TCF1+CD8+ T cells, preventing them from mounting effective anti-cancer responses. Therefore, targeting the PGE2-EP2/EP4 axis emerges as a promising molecular strategy to restore IL-2 responsiveness in tumor-infiltrating anti-cancer CD8+ T cells, ultimately enabling effective immune control of cancer.