Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation.

ABSTRACT: In this study, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAM) through TNFα signaling. Mechanistically, HPGDS installs a prostaglandin D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their protumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces antitumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a protumoral environment and αPD1 resistance, preventing the downregulation of HPGDS by T cells. Congruently,

SUBMITTER: Trotta R 

PROVIDER: S-EPMC12223510 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature