Bayerl et al. showed that tumor-derived prostaglandin E2 (PGE2) induced cDC1 dysfunction locally within the TME and impaired cDC1-mediated orchestration of CD8+ T cell responses. PGE2 receptor (EP2 and EP4) signaling downregulated IRF8 and blocked the ability of cDC1s to produce CXCL9/10 and IL-12, which regulate CD8+ T cell attraction and function. Loss of EP2/EP4-mediated PGE2 signaling selectively in intratumoral cDC1s restored the effective CD8+ T cell response and protective anti-cancer immunity. PGE2-induced cDC1 dysfunction was conserved in humans, where it was correlated with poor survival and decreased response to ICB therapy.
Contributed by Shishir Pant
ABSTRACT: Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell responses within tumors, but it is poorly understood how this function is regulated and whether its subversion contributes to immune evasion. Here, we show that tumor-derived prostaglandin E2 (PGE(2)) programmed a dysfunctional state in intratumoral cDC1s, disabling their ability to locally orchestrate anti-cancer CD8(+) T cell responses. Mechanistically, cAMP signaling downstream of the PGE(2)-receptors EP2 and EP4 was responsible for the programming of cDC1 dysfunction, which depended on the loss of the transcription factor IRF8. Blockade of the PGE(2)-EP2/EP4-cDC1 axis prevented cDC1 dysfunction in tumors, locally reinvigorated anti-cancer CD8(+) T cell responses, and achieved cancer immune control. In human cDC1s, PGE(2)-induced dysfunction is conserved and associated with poor cancer patient prognosis. Our findings reveal a cDC1-dependent intratumoral checkpoint for anti-cancer immunity that is targeted by PGE(2) for immune evasion.
Author Info: (1) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (2) Institute of Molecular Immunology, School of Medicine, Technical Uni
Author Info: (1) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (2) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (3) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany; German Center for Infection Research, Munich, Germany. (4) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (5) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (6) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (7) Institute of Experimental Oncology, School of Medicine, Technical University of Munich, Munich, Germany. (8) Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. (9) Institute for Artificial Intelligence in Medicine & Healthcare, School of Medicine, Technical University of Munich, Munich, Germany. (10) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (11) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (12) Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany. (13) Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany. (14) Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (15) Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (16) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (17) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (18) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. (19) Department for Dermatology, University Hospital Essen, Essen, Germany. (20) Institute of Experimental Oncology, School of Medicine, Technical University of Munich, Munich, Germany. (21) Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany. (22) Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. (23) Department for Dermatology, University Hospital Essen, Essen, Germany. (24) Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (25) Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany. (26) Walter-Brendel Center for Experimental Medicine, LMU Munich, Planegg-Martinsried, Germany; Biomedical Center, Institute for Cardiovascular Physiology and Pathophysiology, LMU Munich, Planegg-Martinsried, Germany. (27) Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address: j.boettcher@tum.de.
