Activated T cells break tumor immunosuppression by macrophage re-education
Here, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAMs) through TNFa signaling. Mechanistically, HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces anti-tumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to aPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFa blockade sustains a pro-tumoral environment and aPD1-resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to aPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient aPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance. Overall design: Bulk RNA sequencing of in vivo sorted Hpgds KO and control tumor-associated macrophages from YUMM 1.7 tumor bearing mice.