Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses

• DOI: 10.1016/j.immuni.2023.05.011
• Publication Date: 2023-06-13T14:44:42Z
• Authors: Felix Bayerl; Philippa Meiser; Sainitin Donakonda; Anna Hirschberger; Sebastian B. Lacher; Anna-Marie Pedde; Chris D. Hermann; Anais Elewaut; Moritz Knolle; Lukas Ramsauer; Thomas J. Rudolph; Simon Grassmann; Rupert Öllinger; Nicole Kirchhammer; Marcel Trefny; Martina Anton; Dirk Wohlleber; Bastian Höchst; Anne Zaremba; Achim Krüger; Roland Rad; Anna C. Obenauf; Dirk Schadendorf; Alfred Zippelius; Veit R. Buchholz; Barbara U. Schraml; Jan P. Böttcher
• Keywords: Neoplasms; Medizin; Humans; Receptors, Prostaglandin E; Dendritic Cells; CD8-Positive T-Lymphocytes; Dinoprostone; Antibodies; 3. Good health

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 (PGE2) 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 PGE2-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 PGE2-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, PGE2-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 PGE2 for immune evasion.