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

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. [Display omitted] •Tumor-derived PGE2 programs mouse and human cDC1 dysfunction through cDC1 loss of IRF8•Dysfunctional cDC1s fail to locally orchestrate anti-cancer CD8+ T cell responses in tumors•Signaling through the PGE2-receptors EP2 and EP4 controls cDC1 reprogramming•EP2 and EP4 ablation in cDC1s results in effective anti-cancer CD8+ T cell immunity cDC1s are critical for effective anti-cancer immunity but often dysfunctional in tumors. Bayerl et al. reveal that PGE2 controls cDC1 function locally in tumors through the downregulation of IRF8, limiting cDC1-dependent anti-cancer CD8+ T cell responses, and show that preventing PGE2-induced cDC1 dysfunction elicits effective CD8+ T cell-mediated tumor immune control.