Prostaglandin E2 induces dendritic cell dysfunction in skin involvement of breast cancer.

The skin involvement (SI) of breast cancer exhibits suboptimal to standard treatment and poor prognosis. Dendritic cells (DCs) are essential to maintain immune homeostasis. However, the role of cutaneous DCs in skin lesions of breast cancer remains elusive, limiting the development of therapeutic approaches. Here, skin tissues from 47 breast cancer patients were analyzed for different immune cell infiltration, showing a significant reduction in DC number and activation in lesional skin. Transcriptome analyses, in vitro antigen processing and T lymphocyte priming assays of primary cutaneous DCs from breast cancer patients corroborated impaired antigen processing and T lymphocyte priming in lesional skin. Mechanistically, metabolomic analyses profiled the microenvironment of lesional and non-lesional skin and revealed increased prostaglandin E2 (PGE2) levels in the lesional skin, which could inhibit DC activation. Inhibiting PGE2 in vivo effectively restored the activation of DCs and CD8+ T lymphocytes and attenuated the skin involvement in mouse models of different cancer types. Clinically, the PGE2 levels were negatively correlated with DC infiltration in the skin of breast cancer patients, and low PGE2 expression and high DC activation were associated with better patient outcomes. Collectively, our study reveals that PGE2 induces DC dysfunction in the skin involvement of breast cancer, highlighting the potential of targeting PGE2 for managing patients with skin involvement. A schematic diagram illustrating PGE2 induced DC dysfunction in the skin. PGE2 induces DC dysfunction in the skin involvement of breast cancer, and PGE2 inhibition restores DC activation and relieves skin involvement. Ag, antigen; CD, cluster of differentiation; DC, dendritic cell; MHC, major histocompatibility complex; PGE2, prostaglandin E2.