| First Author | Trotta R | Year | 2025 |
| Journal | Cancer Discov | Volume | 15 |
| Issue | 7 | Pages | 1410-1436 |
| PubMed ID | 40094380 | Mgi Jnum | J:369085 |
| Mgi Id | MGI:8218165 | Doi | 10.1158/2159-8290.CD-24-0415 |
| Citation | Trotta R, et al. (2025) Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation. Cancer Discov 15(7):1410-1436 |
| abstractText | 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 TNFalpha 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 alphaPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFalpha blockade sustains a protumoral environment and alphaPD1 resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to alphaPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient alphaPD1 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. SIGNIFICANCE: In this study, we show a mechanism whereby T-cell activation controls the innate immune system and shapes the tumor microenvironment by reducing PGD2 production in TAMs. We suggest HPGDS inhibition as a promising strategy to treat refractory tumors to current immunotherapies or to overcome acquired resistance to immune checkpoint blockade. |
