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

著者: Felix Bayerl, Philippa Meiser, Sainitin Donakonda, Anna Hirschberger, Sebastian Lacher, Anna‐Marie Pedde, Chris D. Hermann, Anais Elewaut, Moritz Knolle, Lukas Ramsauer, Thomas Rudolph, Simon Grassmann, Rupert Öllinger, Nicole Kirchhammer, Marcel P. 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 - Immunity 2023 被引用: 177

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.