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

Felix Bayerl1, Philippa Meiser1, Sainitin Donakonda2

  • 1Institute of Molecular Immunology, School of Medicine, Technical University of Munich, Munich, Germany.

Immunity
|June 14, 2023
PubMed

Insights

Tumor-derived prostaglandin E2 (PGE2) disables cancer-fighting dendritic cells (cDC1s) by disrupting T cell responses. Blocking this pathway restores anti-cancer immunity and improves tumor control.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Signaling

Background:

  • Type 1 conventional dendritic cells (cDC1s) are crucial for initiating anti-cancer immune responses.
  • The regulation of cDC1 function within the tumor microenvironment and its subversion by tumors remain poorly understood.
  • Understanding these mechanisms is vital for developing effective cancer immunotherapies.

Purpose of the Study:

  • To investigate how tumor-derived factors regulate cDC1 function in anti-cancer immunity.
  • To elucidate the molecular mechanisms by which cDC1 anti-cancer functions are suppressed.
  • To explore therapeutic strategies targeting cDC1 dysfunction for cancer immune control.

Main Methods:

  • Analysis of intratumoral cDC1s from tumor models.
  • Investigating the role of prostaglandin E2 (PGE2) and its receptors (EP2/EP4) in cDC1 programming.
  • Assessing the impact of IRF8 (interferon regulatory factor 8) on cDC1 function.
  • Evaluating the efficacy of blocking the PGE2-EP2/EP4-cDC1 axis in vivo.

Main Results:

  • Tumor-derived PGE2 induces a dysfunctional state in intratumoral cDC1s, impairing their ability to support CD8+ T cell responses.
  • This cDC1 dysfunction is mediated by cAMP signaling downstream of EP2 and EP4 receptors and involves the loss of IRF8.
  • Blocking the PGE2-EP2/EP4-cDC1 pathway restores cDC1 function, enhances anti-cancer CD8+ T cell responses, and achieves tumor immune control.
  • PGE2-induced cDC1 dysfunction is conserved in human cancers and correlates with poor patient prognosis.

Conclusions:

  • Tumor-derived PGE2 acts as a key immunosuppressive factor by reprogramming cDC1s into a dysfunctional state.
  • The PGE2-EP2/EP4-cAMP-IRF8 signaling axis represents a critical checkpoint for anti-cancer immunity within the tumor microenvironment.
  • Targeting this axis offers a promising therapeutic strategy to overcome tumor immune evasion and enhance cancer immunotherapy.
Keywords:
T cellscancer immunotherapydendritic cellsimmune evasionprostaglandin E2tumor microenvironment

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